Literature Report for an ALS gene set
Introduction (back to top)

This literature report is generated for a set of concepts that you have a particular interest in. This Start Set is provided by you. The Start Set consists of concepts such as human genes, metabolites, pathways, bacteria, phenotypes and diseases. This report helps in the look-up of the relevant literature for your Start Set: it displays abstracts about each of your concepts and all inter-connections. Next, relations between the concepts of your Start Set and concepts that are part of our BioSets are described. BioSets are expert-curated sets of different biological concepts that describe a certain topic. Examples of BioSets that can optionally be included are: gut health, skin health, brain health, oncology and immunity. Finally, relations between the concepts of your Start Set and the Discovery Set are described. The Discovery Set contains over 200,000 biological concepts that are the basis of our KMAP database. The above is described in the overview picture below:

The report has been divided into several sections, designed to answer specific questions. These are listed below, you can click on the links to directly jump to a specific section.

What is known about the members of my set?
How are the concepts related to each other?
Which facts are known about the members of my set?
How are my concepts related to BioSets?
How is each concept related to new concepts?

What is known about the members of my set? (back to top)
The table below lists the concepts in your Start Set. For each of the concepts, the names and its synonyms (if any) are shown. The name of each concept is hyperlinked to a TenWise literature overview page for this concept. You can use the buttons to export the Start Set to another program. You can also use the search box to search for a concept in your set. When you type in a part of the word in this box, the table is automatically filtered and updated.

Set member Synonyms
CCL19CKb11; ELC; MIP-3Beta; MIP-3b; MIP-3beta; SCYA19; exodus-3
IL22RA1CRF2-9; IL22R
IL22IL-21; IL-22; IL-D110; IL-TIF; ILTIF; MGC79382; MGC79384; TIFIL-23; TIFa; zcyto18
IL21IL-21; Za11
C9orf72DENND9; DENNL72; MGC23980
How are the concepts related to each other? (back to top)
The table below shows how each concept is connected with all other concepts in you Start Set. The table works as follows. Each of the concepts from your set is listed in the table in the left panel. The number between parentheses shows the number of other concepts in your set that it has a connection to. Clicking on the ">" link displays the actual members on the right hand side, each with a separate link. Clicking on this link brings you to the TenWise Literature overview page that shows the abstracts in which the relation between the two concepts are described.

The network below is a visual representation of the data that are shown in the section above. You can use the controller in the top left corner to zoom and shift the network. You can also drag the nodes in the network to alter the position of the nodes. Clicking on a single node opens a new window in which the most relevant abstracts for that node are shown.
Clicking on the lines that connect 2 nodes opens up a window in which the abstracts are shown in which both nodes co-occur.

Which facts are known about the members of my set? (back to top)
This section lists individual sentences that were obtained from all abstracts in which a concept of your Start Set was mentioned together with a BioSet concept. You can use the search box to filter for specific words. The leftmost columns links directly to the PubMed abstract.

11035029Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.
11035029Interleukin-10 (IL-10)-related T cell-derived inducible factor (IL-TIF; provisionally designated IL-22) is a cytokine with limited homology to IL-10.
11035029We report here the identification of a functional IL-TIF receptor complex that consists of two receptor chains, the orphan CRF2-9 and IL-10R2, the second chain of the IL-10 receptor complex.
11035029However, in hamster cells both chains, CRF2-9 and IL-10R2, must be expressed to assemble the functional IL-TIF receptor complex.
11035029The CRF2-9 chain (or the IL-TIF-R1 chain) is responsible for Stat recruitment.
11035029Substitution of the CRF2-9 intracellular domain with the IFN-gammaR1 intracellular domain changes the pattern of IL-TIF-induced Stat activation.
11035029The CRF2-9 gene is expressed in normal liver and kidney, suggesting a possible role for IL-TIF in regulating gene expression in these tissues.
11390454Cross-linking experiments demonstrate that the protein binds IL-22 and prevents binding of IL-22 to the functional cell surface IL-22R complex, which consists of two subunits, the IL-22R1 and the IL-10R2c chains.
11390454Moreover, this soluble receptor, designated IL-22-binding protein (BP), is capable of neutralizing IL-22 activity.
11390454In the presence of the IL-22BP, IL-22 is unable to induce Stat activation in IL-22-responsive human lung carcinoma A549 cells.
11390454Thus, the soluble receptor designated IL-22BP inhibits IL-22 activity by binding IL-22 and blocking its interaction with the cell surface IL-22R complex.
11798462These results support the conclusion that IL-10Rbeta is a required common component of both the IL-10 and IL-22 receptors and suggest that IL-22 may play a role in the immune response in pancreas.
11970879IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity.
11970879We now report that IL-21, a product of activated T cells, may serve this function.
11970879Mice lacking IL-21R (IL-21R(-/-)) had normal NK cell development but no detectable responses to IL-21.
11970879IL-21 enhanced cytotoxic activity and IFNgamma production by activated murine NK cells but did not support their viability, thus limiting their duration of activation.
11970879Furthermore, IL-21 blocked IL-15-induced expansion of resting NK cells, thus preventing the initiation of further innate responses.
11970879These observations suggest that IL-21 promotes the transition between innate and adaptive immunity.
11970980IL-2, IL-4, IL-7, IL-9, IL-15, IL-21), in activation and expansion of CD4(+) and CD8(+) T cells in the allogeneic hosts.
11986233Interleukin-21 (IL-21) is a recently cloned cytokine with homology to IL-2, IL-4, and IL-15.
11986233In this study we examined the effects of IL-21 on human myeloma cells.
11986233We found that IL-21 induced proliferation and inhibited apoptosis of the IL-6-dependent human myeloma cell lines ANBL-6, IH-1, and OH-2.
11986233The potency of IL-21 was close to that of IL-6 in the OH-2 cell line.
11986233Neutralizing antibodies to IL-6 or the IL-6 receptor transducer chain (gp130) did not affect IL-21-induced DNA synthesis, indicating that IL-21-induced proliferation was not mediated through these proteins.
11986233Tumor necrosis factor (TNF), another stimulator of myeloma cell growth, up-regulated the expression level of IL-21 receptor (IL-21R), and combinations of TNF and IL-21 gave synergistic effects on myeloma cell proliferation.
11986233Furthermore, 4 of 9 purified samples of primary myeloma cells showed a significant increase in DNA synthesis on stimulation of the cells by IL-21.
11986233IL-21 is a novel growth and survival factor in multiple myeloma and may represent a target for future therapy.
12047749This response was dependent on costimulatory growth factors, such as interleukin (IL)-2, IL-15 and IL-21.
12047749Significant levels of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were secreted in the presence of IL-2 and IL-15, but not in the presence of IL-21, demonstrating that proliferating phosphoantigen-reactive Vgamma9/Vdelta2 T cells do not necessarily produce proinflammatory cytokines.
12087100Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line.
12087100IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called ZcytoR11/CRF2-9) and IL-10Rbeta (CRF2-4), which is also involved in IL-10 signaling.
12087100We found that IL-22 induces activation of JAK1 and Tyk2 but not JAK2, as well as phosphorylation of STAT1, STAT3, and STAT5 on tyrosine residues, extending the similarities between IL-22 and IL-10.
12393685Interleukin 21 (IL-21) has recently been identified as a multifunctional cytokine that induces the proliferation of T cells and B cells and differentiation of natural killer cells.
12393685To determine whether IL-21 regulates IL-4-mediated immune responses, we examined the effect of IL-21 on antigen-specific IgE production in mice.
12393685We also examined the effect of IL-21 on IL-4-induced IgE production from B cells and antigen-induced T-helper 2 (T(h)2) cell differentiation.
12393685The in vivo injection of IL-21 prevented antigen-specific IgE but not IgG2a production on immunization.
12393685IL-21 did not affect T(h)2 cell differentiation or IL-4 production from CD4(+) T cells but directly inhibited IL-4-induced IgE production from B cells at single-cell levels.
12393685Moreover, IL-21 inhibited IL-4-induced germ line C(epsilon) transcription in B cells without the inhibition of signal transducer and activator of transcription 6 (Stat6) activation.
12393685Taken together, these results indicate that IL-21 down-regulates IgE production from IL-4-stimulated B cells through the inhibition of germ line C(epsilon) transcription and thus suggest that IL-21 may be useful for the treatment of IgE-dependent allergic diseases.
12429707Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses.
12429707IL-21 is produced by activated T cells, and it influences proliferation of T and B cells and cytolytic activity of natural killer cells.
12429707The elucidation of the unique biological effects of IL-21 represents an intense area of interest in current cytokine biology.
12446913IL-21 in regulating immunoglobulin production.
12446913We demonstrate that, although mice deficient in the receptor for IL-21 (IL-21R) have normal lymphoid development, after immunization, these animals have higher production of the immunoglobulin IgE, but lower IgG1, than wild-type animals.
12446913Thus, IL-21 has a significant influence on the regulation of B cell function in vivo and cooperates with IL-4.
12504082Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain.
12504082Interleukin 21 (IL-21) is a recently identified novel cytokine that plays an important role in the regulation of B, T, and NK cell functions.
12504082The formation of a binary complex between IL-21 and immobilized IL-21R (K(D) 70pM), gamma(c) and immobilized IL-21 (K(D) 160 microM) and a ternary complex between gamma(c) and IL-21 saturated immobilized IL-21R (K(D) 160nM) could be analyzed.
12504082The gamma(c) residues involved in IL-21 binding were defined by alanine-scanning mutational analysis.
12513909Interleukin-22 (IL-22) is a cellular homolog of IL-10 that stimulates the production of acute-phase reactants.
12513909IL-22 and IL-10 require different ligand-specific receptor chains (IL-22R and IL-10R1) but share a second receptor chain (IL-10R2) to initiate cellular responses.
12513909The quaternary structures and the ability of IL-22 and IL-10 to engage soluble (s) IL-10R1, IL-22R, IL-10R2 receptor chains were analyzed using size exclusion chromatography and surface plasmon resonance techniques.
12513909In contrast, IL-10R2 exhibits essentially no affinity for IL-22 (K(eq) approximately 1 mM) or IL-10M1 (K(eq) approximately 2 mM) alone but displays a substantial increase in affinity for the IL-10/sIL-10R1 (K(eq) approximately 350 microM) and IL-22/sIL-22R (K(eq) approximately 45 microM) complexes.
12521379This gene, termed likely interleukin or cytokine receptor-2 ( LICR2 ), is located on chromosome 1, at 25 kb from the IL22R (IL-22 receptor) gene, and is constitutively expressed in most tissues.
12635355Recently, new inflammation modulator cytokines were described: IL-20, IL-21, IL-22 and IL-23.
12635355IL-21 and IL-15 are important in NK cells differentiation.
12637939Interleukin-21 (IL-21) is a novel cytokine that can induce proliferation of activated T cells and maturation of natural killer (NK) cells.
12637939We therefore examined whether expression of the IL-21 gene in tumor cells could generate antitumor responses.
12637939Murine colon carcinoma Colon 26 cells that were transduced with the mouse IL-21 gene (Colon 26/IL-21) were rejected in syngeneic mice and the mice subsequently acquired protective immunity.
12637939The growth of Colon 26/IL-21 tumors developed in nude mice was retarded compared with that of parent tumors, and this growth suppression was not observed in nude mice that were treated with anti-asialo GM(1) antibody.
12637939Spleen cells from the mice that had rejected Colon 26/IL-21 cells showed cytotoxic activity to Colon 26 but not to irrelevant tumor cells, and produced larger amounts of interferon-gamma upon stimulation with irradiated Colon 26 cells.
12637939Spleen cells from Colon 26/IL-21-tumor- but not parent-tumor-bearing mice had lytic activity to YAC-1 cells.
12637939These data suggest that expression of IL-21 in tumors induces T- and NK-cell-dependent antitumor effects.
12893770Interleukin 21 (IL-21) is a newly described cytokine with homology to IL-4 and IL-15.
12893770Since it is well known that IL-4 modulates differentiation and activation of dendritic cells (DCs), we analyzed effects of IL-21 compared with IL-15 on DC differentiation, maturation, and function.
12893770Here we show that DCs generated with granulocyte-macrophage colony-stimulating factor (GMCSF) in the presence of IL-21 (IL-21DCs) differentiated into phenotypically and functionally altered DCs characterized by reduced major histocompatibility complex class II (MHCII) expression, high antigen uptake, and low stimulatory capacity for T-cell activation in vitro.
12893770Furthermore, IL-21 blocked lipopolysaccharide (LPS)-induced activation and maturation of DCs, which was not mediated by release of the anti-inflammatory cytokine IL-10.
12893770Taken together, these results identify a dichotomous action of these structurally related cytokines on DCs, establishing IL-21 as inhibitory cytokine on DC activation and IL-15 as potent stimulator of DC function, making both cytokines interesting targets for therapeutic manipulation of DC-induced immune reactions.
12969638Bovine interleukin-21 (IL-21) cDNA was cloned and sequenced from bovine peripheral blood lymphocytes (PBLs) stimulated with 10 microg/ml concanavalin A (ConA), 10 microg/ml phytohemagglutinin (PHA), and 50 ng/ml phorbol 12-myristate 13-acetate (PMA) for 48 h.
12969638The open reading frame of the bovine IL-21 cDNA is 459 bp in length and encodes 152 amino acids.
12969638IL-21 amino acid sequences, respectively.
12969638Recombinant bovine IL-21 was expressed by a baculovirus expression system.
12969638The bovine IL-21 was processed to the mature form in insect cells and secreted to the supernatant confirmed by N-terminal amino acid sequencing.
12969638The mRNA expression for bovine IL-21 was observed in the spleen, but not in the brain, heart, lung, liver, and kidney.
12969638The bovine IL-21 identified in this study may provide new methods for the enhancement of innate immunity in cows.
14502230Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects.
14502230Human pancreatic cancer AsPC-1 cells were retrovirally transduced with murine IL-21 or IL-23 (p19-linked p40) gene (AsPC-1/IL-21, AsPC-1/IL-23) and were injected into nude or severe combined immunodeficiency (SCID) mice.
14502230Although the proliferation in vitro of the transduced cells remained the same as that of parent cells, growth of AsPC-1/IL-21 and AsPC-1/IL-23 tumors developed in nude mice was retarded compared with that of parent tumors.
14502230Treatment of nude mice with anti-asialo GM(1) antibody temporally abrogated the growth retardation of AsPC-1/IL-21, but not AsPC-1/IL-23 tumors; however, the growth of AsPC-1/IL-21 tumors came to be retarded thereafter with the regeneration of natural killer (NK) cells.
14502230The growth of AsPC-1/IL-21 tumors developed in SCID mice was also retarded compared with parent tumors and the growth retardation was abrogated by treatment with anti-asialo GM(1) antibody.
14502230Cytotoxic activity and secretion of interferon-gamma in response to AsPC-1 cells were induced in spleen cells of the mice bearing AsPC-1/IL-21 or AsPC-1/IL-23 tumors.
14502230When nude mice were injected with a mixed population of AsPC-1/IL-21 and AsPC-1/IL-23 cells, no synergistic effects were observed.
14502230These data collectively suggest that expression of IL-21 and IL-23 in tumors can produce NK cell-dependent and -independent antitumor effects in an alpha beta T cell-defective condition, respectively.
14642651Immunohistochemical study on the distribution of insulin-like growth factor I (IGF-I) receptor in the central nervous system of SOD1(G93A) mutant transgenic mice.
14642651In the present study, we used the SOD1(G93A) mutant transgenic mice as an in vivo model of ALS and performed immunohistochemical studies to investigate the changes of insulin-like growth factor I (IGF-I) receptor in the central nervous system.
14657853IL-21: a novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses.
14657853IL-21 is a recently described type I cytokine produced by activated CD4(+) T cells that profoundly affects the growth, survival, and functional activation of B, T, and natural killer lymphocytes in concert with other cytokines or activating stimuli.
14657853Structurally, IL-21 is predicted to display a 4-helix-bundle-type fold with significant homology to IL-2, IL-4, and IL-15 and mediates its biologic effects through a novel type I cytokine receptor, IL-21R, in conjunction with the common cytokine receptor gamma chain (gammac) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors.
14657853As a new member of the gammac-dependent cytokine family, there is significant interest in IL-21, in part because of its potential to provide new insights into the immunologic phenotype caused by gammac deficiency.
14657853As expected for cytokines that use gammac, recent studies indicate that IL-21 induces Janus kinase 1 (JAK1) and JAK3 activation to initiate signal transduction, but unlike these other gammac-dependent cytokines, which predominantly activate signal transducer and activator of transcription 5 (STAT5), IL-21 preferentially activates STAT1 and STAT3.
14657853IL-21 potently enhances primary antigen responses and the effector functions of T and natural killer cells and stimulates IFN-gamma production alone or in concert with other cytokines.
14657853Thus, on the basis of primary structure, receptor composition, and biologic activities, IL-21 is a new IL-2-family cytokine that participates in both innate and adaptive immunity and might be important for the development of a T(H)1 immune response.
14675186We here analyzed the role of IL-21 in dendritic cell (DC)-induced, T cell-mediated contact hypersensitivity (CHS) in vivo and on T cell activation and unspecific mixed lymphocyte reaction in vitro.
14675186By PCR, we demonstrate here constitutive expression of the specific IL-21 receptor and the common gamma-chain in DC, which together are able to mediate IL-21 signaling.
14675186Short-time incubation of in vitro generated DC with IL-21 significantly reduced their potential to induce an antigen-specific CD8+ T cell proliferation.
14675186Interestingly, 2h incubation of these DC with IL-21 before injection completely inhibited the potential of these DC to induce a CHS reaction to the hapten fluorescein 5-isothiocyanate in vivo.
14675186Our data demonstrate that IL-21 is a new modulator of DC-T cell interaction with the potential to induce DC-mediated antigen-specific tolerance.
14695220IL-21 is a more recently discovered cytokine produced by activated CD4(+) T cells that shares significant sequence homology to IL-2, IL-4, and IL-15.
14695220Because IL-21 and IL-2 and their receptors share significant sequence similarities and both cytokines can stimulate T and natural killer (NK) cells, we sought to study whether IL-21, like IL-2, exhibits antitumor effects in vivo.
14695220DNA encoding murine IL-21 using a hydrodynamics-based gene delivery technique.
14695220Administration of IL-21 plasmid DNA resulted in high levels of circulating IL-21 in vivo.
14695220In vivo depletion of either CD4(+) or CD8(+) T cells did not affect IL-21-mediated antitumor activity.
14695220However, depletion of NK cells completely abolished IL-21-induced tumor inhibition.
14695220Consistent with this, the antitumor activity of IL-21 seemed to be mediated through enhanced cytolytic activity of NK cells.
14695220Our study suggests that IL-21 has significant antitumor activity and may have therapeutic potentials as an antitumor agent in the clinic.
14734732IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice.
14734732IL-21 is an immune-stimulatory four alpha helix cytokine produced by activated T cells.
14734732Five days after injection, TS/A-IL-21 tumors showed numerous infiltrating granulocytes, NK cells, and to a lesser extent CD8(+) T cells, along with the expression of TNF-alpha, IFN-gamma, and endothelial adhesion molecules ICAM-1 and VCAM-1.
14734732The TS/A-IL-21 tumor displayed a disrupted vascular network with abortive sprouting and signs of endothelial cell damage.
14734732In vivo depletion experiments by specific Abs showed that rejection of TS/A-IL-21 cells required CD8(+) T lymphocytes and granulocytes.
14734732When injected in IFN-gamma-deficient mice, TS/A-IL-21 cells formed tumors that regressed in only 29% of animals, indicating a role for IFN-gamma in IL-21-mediated antitumor response, but also the existence of IFN-gamma-independent effects.
14734732Most immunocompetent mice rejecting TS/A-IL-21 cells developed protective immunity against TS/A-pc (75%) and against the antigenically related C26 colon carcinoma cells (61%), as indicated by rechallenge experiments.
14734732CTL response against the gp70-env protein of an endogenous murine retrovirus coexpressed by TS/A and C26 cells was detected in mice rejecting TS/A-IL-21 cells.
14734732These data suggest that IL-21 represents a suitable adjuvant in inducing specific CTL responses.
15100251Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells.
15100251IL-21 is a cytokine that regulates the activation of T and NK cells and promotes the proliferation of B cells activated via CD40.
15107555IL-21) cDNA was successfully cloned and sequenced from porcine peripheral blood lymphocytes (PBL) stimulated with 10 microg/ml concanavalin A (ConA), 10 microg/ml phytohemagglutinin P (PHA), 50 ng/ml phorbol 12-myristate 13-acetate (PMA), and 0.
15107555The open reading frame of the porcine IL-21 cDNA is 459 base pairs in length and encodes 152 amino acids.
15107555The predicted amino acid sequence of the porcine IL-21 shows 86.
15107555IL-21, respectively.
15107555The porcine IL-21 gene was mapped to porcine chromosome 8 (8q22-->q23) by means of fluorescence in situ hybridization and radiation hybrid mapping, where the porcine IL-2 gene had been mapped nearby.
15107555The porcine IL-21 identified in this study will be helpful for the enhancement of innate immune responses of pigs.
15120653Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2.
15120653Interleukin 22 (IL-22) is a cytokine induced during both innate and adaptive immune responses.
15120653IL-22 requires the presence of the IL-22 receptor (IL-22R) and IL-10 receptor 2 (IL-10R2) chains, two members of the class II cytokine receptor family (CRF2), to effect signal transduction within a cell.
15120653IL-22 has measurable affinity for IL-22R-Fc homodimer and undetectable affinity for IL-10R2.
15120653IL-22 has substantially greater affinity for IL-22R/IL-10R2-Fc heterodimers.
15120653Further analyses involving sequential additions of receptor homodimers and cytokine indicates that the IL-10R2(ECD) binds to a surface created by the interaction between IL-22 and the IL-22R(ECD), and thereby further stabilizes the association of IL-22 within this cytokine-receptor-Fc complex.
15146416Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis.
15146416Of note, IL-21 was not detectable by real-time PCR and in situ hybridization in the same samples in vivo as in vitro.
15201862We have identified the mouse and rat homologs of human interleukin-22 receptor alpha 2 (IL-22R alpha 2) and compared the localization, structure, and expression of the encoding murine and human genes.
15207081SDS-PAGE analysis showed the IL-21 was expressed in the form of insoluble inclusion body.
15210829Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis.
15210829IL-21 costimulates B cell proliferation and cooperatively with IL-4 promotes T cell-dependent Ab responses.
15210829Somewhat paradoxically, IL-21 also induces apoptosis of B cells.
15210829The present study was undertaken to more precisely define the expression of the IL-21R, using a novel mAb, and the circumstances by which IL-21 promotes B cell growth vs death.
15210829Functional studies demonstrated that IL-21 substantially inhibited proliferation and induced Bim-dependent apoptosis for LPS or CpG DNA-activated B cells.
15210829In contrast, IL-21 induced both costimulation and apoptosis for anti-CD40-stimulated B cells, whereas IL-21 primarily costimulated B cells activated by anti-IgM or anti-IgM plus anti-CD40.
15210829Upon blocking apoptosis using C57BL/6 Bim-deficient or Bcl-2 transgenic B cells, IL-21 readily costimulated responses to anti-CD40 while proliferation to LPS was still inhibited.
15210829Engagement of CD40 or the BCR plus CD40 prevented the inhibitory effect by IL-21 for LPS-activated B cells.
15210829Collectively, these data indicate that there are three separable outcomes for IL-21-stimulated B cells: apoptosis, growth arrest, or costimulation.
15210829We favor a model in which IL-21 promotes B cell maturation during a productive T cell-dependent B cell response, while favoring growth arrest and apoptosis for nonspecifically or inappropriately activated B cells.
15470476DNA encoding IL-12, IL-15, IL-18 or IL-21 was capable of elevating survival rates of HSV-1-infected mice when coinjected with 1 microg of gB pDNA, while IL-10 gene delivery failed to affect the effectiveness of the genetic immunization.
15541036We examined whether expression of the IL-22 gene in murine colon carcinoma Colon 26 cells (Colon 26/IL-22) could produce any antitumour effects in the inoculated mice.
15541036Although growth of Colon 26/IL-22 tumours in syngeneic mice was not different from that of parent tumours, survival of the mice that were subcutaneously or intraperitoneally inoculated with Colon 26/IL-22 tumours was significantly prolonged compared with the mice inoculated with parent tumours.
15541036Expression of the IL-22 receptor-specific gene, IL-22R, was not induced in spleen cells stimulated with concanavalin A, anti-CD3 or anti-CD40 antibody, despite constitutive expression of the IL-10R2 gene, which encodes another component of the heterodimeric IL-22 receptor complex.
15541036IL-22 thereby does not directly act on immunocompetent cells, and IL-22 expressed in tumours can favour apothanasia of inoculated hosts.
15546386The most common form of SCID, X-linked SCID, results from mutations in the common cytokine receptor gamma-chain, which is shared by the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, underscoring that X-linked SCID is indeed a disease of defective cytokine signaling.
15546387Biology of IL-21 and the IL-21 receptor.
15546387Interleukin-21 (IL-21) is the newest member of the common gamma-chain family of cytokines, which includes IL-2, IL-4, IL-7, IL-9, IL-13, and IL-15.
15546387Initial studies have demonstrated that IL-21 has pleiotropic effects on the proliferation, differentiation, and effector functions of B, T, natural killer, and dendritic cells.
15546387More recently, the potential therapeutic capacity of IL-21 in the treatment of cancers has been widely investigated.
15546387The biological role of IL-21 in the immune system is complex, as IL-21 has been shown to have the ability to both promote and inhibit immune responses.
15546387Overall, the current data point to IL-21 being a novel immunomodulatory cytokine, whose regulation of any given immune response is highly dependent on the surrounding environmental context.
15638850Interleukin-21 (IL-21) and its receptor (IL-21R) have been recently described.
15638850In this study, we examined the expression of IL-21R and the effect of IL-21 on ATL cells.
15638850In contrast to the expression of IL-21R, IL-21 mRNA was scarcely detectable in these cells.
15638850Concerning the intracellular signalling pathways, IL-21 activated the phosphorylation of the signal transducers and activators of transcription (STAT)3 and STAT5.
15657392Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model.
15657392Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective degeneration of motor neurons, atrophy, and paralysis of skeletal muscle.
15657392Although a significant proportion of familial ALS results from a toxic gain of function associated with dominant SOD1 mutations, the etiology of the disease and its specific cellular origins have remained difficult to define.
15657392Here, we show that muscle-restricted expression of a localized insulin-like growth factor (Igf) -1 isoform maintained muscle integrity and enhanced satellite cell activity in SOD1(G93A) transgenic mice, inducing calcineurin-mediated regenerative pathways.
15728477Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen.
15728477The cytokine IL-21 is closely related to IL-2 and IL-15, a cytokine family that uses the common gamma-chain for signaling.
15728477IL-21 is expressed by activated CD4(+) T cells.
15728477We examined the role of IL-21 in the autoimmune disease experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis.
15728477Autoreactive T cells purified from IL-21-treated mice transferred more severe EAE than did the control encephalitogenic T cells.
15728477No such effects were observed when IL-21 was administered after EAE progressed.
15728477Additional studies demonstrated that IL-21 given before the induction of EAE boosted NK cell function, including secretion of IFN-gamma.
15728477Depletion of NK cells abrogated the effect of IL-21.
15728477Therefore, IL-21, by affecting NK cells, has differential effects during the initiation and progression of autoimmune responses against neuroantigens.
15751077The expression pattern of IL-21/IL-21R was analyzed by in situ hybridization and Western blotting.
15751077Stimulation experiments were performed with cultured dermal fibroblasts from patients with SSc and healthy controls as well as with keratinocytes, using IL-1beta, platelet-derived growth factor BB, monocyte chemoattractant protein 1, transforming growth factor beta, and IL-21.
15751077Interestingly, mRNA for IL-21 could not be detected by real-time PCR and in situ hybridization.
15765404In this study, we examined the expression and role of IL-21, a T-cell-derived cytokine of the IL-2 family; in tissues and cells isolated from patients with inflammatory bowel disease.
15765404METHODS: IL-21 was examined by Western blotting in whole mucosa and lamina propria mononuclear cells (LPMCs) from patients with CD, ulcerative colitis (UC), and controls.
15765404We also examined the effects of exogenous IL-12 on IL-21 production, as well as the effects of blocking IL-21 with an IL-21-receptor Ig fusion protein.
15765404RESULTS: IL-21 was detected in all samples, but its expression was higher at the site of disease in CD in comparison with UC and controls.
15765404Enhanced IL-21 was seen in both ileal and colonic CD and in fibrostenosing and nonfibrostenosing disease.
15765404IL-12 enhanced IL-21 in normal lamina propria lymphocytes through an IFN-gamma-independent mechanism, and blocking IL-12 in CD LPMCs decreased anti-CD3-stimulated IL-21 expression.
15765404Neutralization of IL-21 in CD LPMC cultures decreased phosphorylated STAT4 and T-bet expression, thereby inhibiting IFN-gamma production.
15879595The IL-21 gene is adjacent to the IL-2 gene, and like IL-2, IL-21 is strongly induced at the transcriptional level after T cell activation.
15879595Interestingly, however, in contrast to the IL-2 gene, a calcium ionophore alone was sufficient to induce IL-21 gene expression in preactivated T cells.
15879595Two DNase I hypersensitivity sites were found in the IL-21 gene, corresponding to nucleotide sequences that are conserved in humans and mice.
15879595One site is located at the IL-21 promoter region and conferred T cell receptor-mediated IL-21 gene transcription.
15879595TCR-induced IL-21 gene expression was inhibited by cyclosporin A and FK506.
15879595Thus, our studies reveal that in contrast to IL-2, a calcium signal alone is sufficient to mediate induction of the IL-21 in preactivated T lymphocytes and that this induction appears to result from specific NFAT binding.
15967825In a series of experimental and spontaneous metastases models in mice, we demonstrate far superior antitumor activity of the alpha-GalCer/IL-21 combination above either agent alone.
15967825Transfer of alpha-GalCer-pulsed dendritic cells (DCs) followed by systemic IL-21 caused an even more significant reduction in established (day 8) metastatic burden and prolonged survival.
15967825Combinations of IL-21 with other NK cell-activating cytokines, such as IL-2 and IL-12, were much less effective in the same experimental metastases models, and these cytokines did not substitute effectively for IL-21 in combination with alpha-GalCer.
15990113Insulin-like growth factor (IGF)-1 has been shown to have a protective effect on motor neurons both in vitro and in vivo, but has limited efficacy in patients with amyotrophic lateral sclerosis (ALS) when given subcutaneously.
15990113To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) with a G93A mutation were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord.
16002671IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells.
16002671We evaluated the influence of the CD4+ Th cell-derived common gamma-chain cytokine IL-21 on cytokine-induced naive CD8+ T cell activation.
16002671Stimulation with IL-21 did not induce division and only slightly increased IL-15-induced proliferation of naive CD8+ T cells.
16002671Strikingly, however, IL-15-induced down-modulation of CD28 was completely prevented by IL-21 at the protein and transcriptional level.
16002671Subsequent stimulation via combined TCR/CD3 and CD28 triggering led to a markedly higher production of IL-2 and IFN-gamma in IL-15/IL-21-stimulated cells compared with IL-15-stimulated T cells.
16002671Our data show that IL-21 modulates the phenotype of naive CD8+ T cells that have undergone IL-15 induced homeostatic proliferation and preserves their responsiveness to CD28 ligands.
16081783IL-21 enhances tumor rejection through a NKG2D-dependent mechanism.
16081783IL-21 is a cytokine that can promote the anti-tumor responses of the innate and adaptive immune system.
16081783Mice treated with IL-21 reject tumor cells more efficiently, and a higher percentage of mice remain tumor-free compared with untreated controls.
16081783In this study, we demonstrate that in certain tumor models IL-21-enhanced tumor rejection is NKG2D dependent.
16081783When engagement of the NKG2D receptor was prevented, either due to the lack of ligand expression on the tumor cells or due to direct blocking with anti-NKG2D mAb treatment, the protective effects of IL-21 treatment were abrogated or substantially diminished.
16081783Specifically, IL-21 only demonstrated a therapeutic effect in mice challenged with a retinoic acid early inducible-1delta-bearing lymphoma but not in mice bearing parental RMA tumors lacking NKG2D ligands.
16081783Furthermore, treatment with a blocking anti-NKG2D mAb largely prevented the therapeutic effect of IL-21 in mice challenged with the 4T1 breast carcinoma, the 3LL lung carcinoma, and RM-1 prostate carcinoma.
16081783By contrast, IL-21 did mediate beneficial effects against both the parental DA3 mammary carcinoma and DA3 tumors transfected with H60, a NKG2D ligand.
16081783We also observed that IL-21 treatment could enhance RMA-retinoic acid early inducible-1delta tumor rejection in RAG-1(-/-) deficient mice, thereby demonstrating that the IL-21-induced protective effect can be mediated by the innate immune system and that, in this case, IL-21 does not require the adaptive immune response.
16081783Collectively, these findings suggest that IL-21 therapy may work optimally against tumors that can elicit a NKG2D-mediated immune response.
16097036BACKGROUND: Interleukin-21 (IL-21) plays important roles in the regulation of T, B, and natural killer (NK) cells.
16097036METHODS: A plasmid vector encoding murine IL-21 was injected intravenously into mice with pre-established HNSCC tumors, either alone or in combination with a vector construct expressing IL-15.
16097036RESULTS: Significant antitumor effects were obtained by repeated transfection with either the IL-21 or the IL-15 gene.
16097036IL-21 induced significant elevation of HNSCC-specific CTL activity, while IL-21 and IL-15 augmented NK activity in an additive manner.
16097036The biological effects of IL-21 may be in sharp contrast to those of conventional Th1 and Th2 cytokines, suggesting intriguing implications of this cytokine for the classical concept of Th1 vs.
16138102The interleukin-21 (IL-21)-IL-21-receptor system was discovered in 2000.
16138102It was immediately of great interest because of the homology of IL-21 to IL-2, IL-4 and IL-15, and of the IL-21-receptor subunit IL-21R to the beta-subunit of the IL-2 receptor, and because the IL-21 receptor also contains the common cytokine-receptor gamma-chain, the protein that is mutated in X-linked severe combined immunodeficiency.
16138102As we discuss, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells.
16142394Interleukin-21 (IL-21) is the most recent member of the common gamma-chain-dependent cytokine family.
16142394We studied the expression of the IL-21 receptor (IL-21R) on peripheral B lymphocytes in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (pSjS), and healthy controls.
16142394In some SLE patients, IL-21-induced proliferation of CD19+ B lymphocytes, in the presence of CD40 stimulation, was impaired.
16235250The role of insulin-like growth factor-1 (IGF-1) in amyotrophic lateral sclerosis (ALS) and its mechanism of action are important from both pathogenic and therapeutic points of view.
16260592Interleukin-21 receptor gene induction in human T cells is mediated by T-cell receptor-induced Sp1 activity.
16260592Interleukin-21 (IL-21) plays important roles in regulating the immune response.
16260592IL-21 receptor (IL-21R) mRNA is expressed at a low level in human resting T cells but is rapidly induced by mitogenic stimulation.
16260592Moreover, mutation of the Sp1 motif markedly reduced IL-21R promoter activity, and Sp1 small interfering RNAs effectively diminished IL-21R expression in activated T cells.
16260592Interestingly, upon T-cell receptor (TCR) stimulation, T cells increased IL-21R expression and Sp1 protein levels while decreasing Sp1 phosphorylation.
16260592These data indicate that TCR-induced IL-21R expression is driven by TCR-mediated augmentation of Sp1 protein levels and may partly depend on the dephosphorylation of Sp1.
16291655Effect of IL-21 on NK cells derived from different umbilical cord blood populations.
16291655IL-21 plays a role in the proliferation and maturation of NK cells developed from hematopoietic stem cells.
16291655In this study, we found that IL-21, in the presence of physiological concentration of hydrocortisone (HC), has a significant impact on the functions of NK cells derived from umbilical cord blood (CB) populations.
16291655We demonstrate that IL-21, in combination with Flt3-ligand, IL-15 and HC, induces high proliferative responses and, apart from enhancing NK-mediated cytotoxicity, it also induces a significant increase in lymphokine-activated killer activity of CB/CD34+-derived CD56+ cells.
16291655In addition, IL-21 induced changes in the CD56+ cell cytokine secretion profile.
16291655IFN-gamma production was also modified by IL-21, depending on the presence or absence of IL-18.
16291655Our data ascribe to IL-21 an essential role on NK cell development and function under conditions similar to the in vivo CB microenvironment.
16293216Interleukin-21 (IL-21) is a recently characterized T cell-derived cytokine with a significant homology to IL-2, IL-4 and IL-15.
16293216To determine whether IL-21 has broad immunoregulatory activity and can stimulate durable antitumour responses, we constructed mouse IL-21 (mIL-21) recombinant plasmid and evaluated its antitumor efficacy.
16293216IL-21 was constructed and transfected into Sp2/0 cells.
16293216Mouse IL-21 expression was analyzed by Western blotting and its activities were detected by 3H-TdR incorporation and MTT assay.
16293216IL-21 was injected s.
16293216IL-21 treated mice.
16293754Consistent with its role as a shared receptor for IL-4, IL-7, IL-9, IL-15, and IL-21, gammac forms degenerate contacts with IL-2.
16339522IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells.
16339522IL-21 is a type I cytokine that influences the function of T cells, NK cells, and B cells.
16339522In this study, we report that IL-21 plays a major role in stimulating the differentiation of human B cells.
16339522When human B cells were stimulated through the BCR, IL-21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells.
16339522In contrast, after CD40 engagement, IL-21 induced extensive proliferation, class switch recombination (CSR), and plasma cell differentiation.
16339522Upon cross-linking both BCR and CD40, IL-21 induced the largest numbers of plasma cells.
16339522IL-21 drove both postswitch memory cells as well as poorly responsive naive cord blood B cells to differentiate into plasma cells.
16339522The effect of IL-21 was more potent than the combination of IL-2 and IL-10, especially when responsiveness of cord blood B cells was examined.
16339522IL-21 costimulation potently induced the expression of both B lymphocyte-induced maturation protein-1 (BLIMP-1) and activation-induced cytidine deaminase as well as the production of large amounts of IgG from B cells.
16339522Despite the induction of activation-induced cytidine deaminase and CSR, IL-21 did not induce somatic hypermutation.
16339522Finally, IL-2 enhanced the effects of IL-21, whereas IL-4 inhibited IL-21-induced plasma cell differentiation.
16339522Taken together, our data show that IL-21 plays a central role in CSR and plasma cell differentiation during T cell-dependent B cell responses.
16547253IL-21 stimulation also results in down-regulation of antiapoptotic proteins such as Bcl-x(L) and up-regulation of proapoptotic proteins like Bim.
16551679IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells.
16551679Here, we have analyzed the effect of IL-21 and IFN-gamma on lipopolysaccharide (LPS)-induced maturation and cytokine production of human monocyte-derived DCs.
16551679IL-21 and IFN-gamma receptor genes were expressed in high levels in immature DCs.
16551679IL-21 pretreatment also dramatically reduced LPS-stimulated production of tumor necrosis factor alpha, IL-12, CC chemokine ligand 5 (CCL5), and CXC chemokine ligand 10 (CXCL10) but not that of CXCL8.
16551679IL-21 weakly induced the expression Toll-like receptor 4 (TLR4) and translation initiation region (TIR) domain-containing adaptor protein (TIRAP) genes, whereas the expression of TIR domain-containing adaptor-inducing IFN-beta (TRIF), myeloid differentiation (MyD88) 88 factor, or TRIF-related adaptor molecule (TRAM) genes remained unchanged.
16551679However, IL-21 strongly stimulated the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3 genes.
16551679Our results demonstrate that IL-21, a cytokine produced by activated T cells, can directly inhibit the activation and cytokine production of myeloid DCs, providing a negative feedback loop between DCs and T lymphocytes.
16760750Interleukin (IL)-12 and, possibly, IL-23 govern the Th1 cell differentiation, but optimal induction and stabilization of polarized Th1 cells would require additional cytokines, such as IL-15, IL-18 and IL-21.
16761934IL-21 signals through a heterodimer of a unique IL-21 receptor and the common gamma-chain cytokine receptor.
16761934Preclinical murine models suggested strong antitumor activity of IL-21 in renal cell carcinoma, melanoma and other tumor models.
16761934IL-21 antitumor activity was superior to IL-2 in these tumor models.
16761934Phase I clinical trial of IL-21 in humans with metastatic renal cell carcinoma or melanoma began in May 2004.
16761934Preliminary immunological and clinical findings of patients receiving IL-21 will be reviewed.
16772043Combined IL-21 and low-dose IL-2 therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model.
16772043BACKGROUND: In vivo studies have recently demonstrated that interleukin 21 (IL-21) enhances the anti-tumor function of T-cells and NK cells in murine tumor models, and the combined use of IL-21 and IL-15 has resulted in prolonged tumor regression and survival in mice with previously established tumors.
16772043However, the combined anti-tumor effects of IL-21 and low dose IL-2 have not been studied even though IL-2 has been approved for human use, and, at low dose administration, stimulates the proliferation of memory T cells, and does not significantly increase antigen-induced apoptosis or regulatory T cell (Treg) expansion.
16772043This study examined whether recombinant IL-21 alone or in combination with low-dose IL-2 could improve the in vivo anti-tumor function of naïve, tumor-antigen specific CD8+ T cells in a gp100(25-33) T cell receptor transgenic pmel murine melanoma model.
16772043Seven days after vaccination groups of mice received 5 consecutive days of intraperitoneal administration of IL-2 alone (20 x 10(3) IU), IL-21 alone (20 microg) or IL-21 and IL-2.
16772043RESULTS: IL-21 alone and IL-2 alone both delayed tumor progression, but only IL-21 significantly augmented long-term survival (20%) compared to the control group.
16772043At peak expansion (21 days post vaccination), the combination of IL-21 plus IL-2 resulted in a 2- to 3-fold higher absolute number of circulating tumor antigen-specific pmel CD8+ T cells than was stimulated by IL-2 or IL-21 alone.
16772043Pmel CD8+ T cells were predominantly partitioned into central memory (CD62L+/CD127+) or effector-memory (CD62L-/CD127+) phenotypes by day 28-post vaccination in IL-21 + IL-2 treated mice.
16772043CONCLUSION: These observations support the potential use of IL-21 and low-dose IL-2 therapy in combination with a tumor-antigen vaccine and lymphopenic conditioning in future cancer clinical trials to maintain high numbers of anti-tumor memory CD8+ T cells with the potential to sustain long term tumor regression and survival.
16778988The IL-21 receptor augments Th2 effector function and alternative macrophage activation.
16778988The IL-21 receptor (IL-21R) shows significant homology with the IL-4R, and CD4+ Th2 cells are an important source of IL-21.
16778988In vitro, IL-21 significantly augmented IL-4Ralpha and IL-13Ralpha1 expression in macrophages, resulting in increased FIZZ1 mRNA and arginase-1 activity following stimulation with IL-4 and IL-13.
16785506IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-gamma secretion.
16785506We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21.
16785506Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-gamma.
16785506Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay.
16785506IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells.
16785506Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-gamma by NK cells.
16785506Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-gamma.
16785506These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.
16803996It is reasonable to suppose that the cytokine single-nucleotide polymorphisms (SNPs) studied must be considered against a larger genetic background involving other functional SNPs of Th1 regulator elements such as IL-21 and IL-23.
16890725PURPOSE: We developed the genetically modified mouse bladder carcinoma MBT2 (American Type Culture Collection, Manassas, Virginia), which secretes interleukin-21, to investigate the functional activities of interleukin-21 in tumor immunity.
16890725MATERIALS AND METHODS: The IL-21 gene was cloned from activated T cells by reverse transcriptase-polymerase chain reaction, inserted into an expression vector and then introduced into MBT2 using Lipofectamine.
16890725RESULTS: MBT2 cells secreting interleukin-21 (MBT2/IL-21) were completely rejected when subcutaneously injected into syngeneic mice.
16890725MBT2/IL-21 proliferated only when CD8+ T cells were depleted, whereas MBT2/IL-21 proliferation was totally abrogated in mice depleted of CD4+ T cells, natural killer cells or interferon-gamma.
16890725Subcutaneous injection of MBT2/IL-21 treated with mitomycin C remarkably inhibited parental MBT2 tumor growth at the contralateral site.
16890725Cytotoxicity assays using splenocytes from mice that rejected MBT2/IL-21 and the immunohistochemical features of MBT2/IL-21 tumors confirmed that in situ production of interleukin-21 can elicit powerful antitumor activity through CD8+ T-cell activation.
16919968In fish, interleukin (IL)-2, IL-21 and IL-15 genes have recently been identified by in-silico cloning.
16919968IL-2, IL-15 and IL-21 genes.
16943384Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21.
16943384IL-21 distinctively regulates B cell growth and death, and it redundantly functions with IL-4 for IgG production.
16943384IL-4 and IL-21 in vivo, as both are secreted by activated T cells.
16943384IL-21 or the combination of IL-4 and IL-21 inhibited proliferation by purified mouse B cells to LPS or CpG DNA, whereas these cytokines enhanced proliferation after engaging the BCR or CD40.
16943384Although B cell subsets expressed somewhat varied levels of the IL-21 receptor, LPS-stimulated follicular and marginal B cell subsets were also dominantly susceptible to IL-21-induced growth arrest and cell death.
16943384After activation of B cells with CD40 and LPS, IL-4 and IL-21 distinctively regulated the expression of CD23, CD44, and CD138, and they cooperatively promoted IgG1 class-switching and synthesis.
16943384These findings support a model in which the presence of IL-4 and IL-21 inhibits B cells activated by polyclonal innate signals, and they promote B cell expansion and differentiation during T cell-dependent antibody responses, although the individual responses to IL-4 and IL-21 do not always overlap.
16951332IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomesodermin expression.
16951332Exposure of naive Th cell precursors (Thp) to IL-21 inhibits IFN-gamma production from developing Th1 cells.
16951332The inhibition of IFN-gamma seen in IL-21-treated Thp cells is specific as the expression of other Th1 cytokines is unaffected.
16951332In this study, we show that Eomes mRNA and protein are also expressed in developing Th1 cells, and exposure of naive Thp cells to IL-21 results in a decrease in Eomes expression.
16951332Moreover, the repression of Eomes expression by IL-21 is not due to an indirect effect of IL-21 on the expression of IFN-gamma or STAT4 and is independent of STAT1 and T-bet expression.
16951332Finally, we show that ectopic expression of Eomes prevents the inhibition of IFN-gamma production from IL-21-treated Thp cells.
16951332Taken together, these results demonstrate that Eomes plays a role in regulating IFN-gamma production in CD4+ T cells and IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomes expression.
16987670Molecular cloning, characterization and expression analysis of an IL-21 homologue from Tetraodon nigroviridis.
16987670Interleukin-21 (IL-21) is an important immune cytokine that was well characterized in human and mammals, but little is known in fish.
16987670In present study, an IL-21 homologue was cloned and well characterized from Tetraodon nigroviridis.
16987670The full-length Tetraodon IL-21 cDNA was 849bp in size, containing an open reading frame (ORF) of 438bp that translated a 145 amino-acid peptide, a 5' untranslated region (UTR) of 69bp, and a 3' UTR of 342bp.
16987670The deduced peptide shared identity of 20-49% with other known IL-21 sequences.
16987670The Tetraodon IL-21 gene had six exons while both human and Takifugu IL-21 gene contained only five exons.
16987670In vivo expression study showed that Tetraodon IL-21 mRNAs were constitutively expressed at a low level and only in limited tissues, including gut, gill and gonad in healthy fish, and stimulation with LPS increased the expression of IL-21 in these tissues and induced the expression of IL-21 in kidney, spleen and skin, indicating that IL-21 is an inflammatory stress inducible gene associated with the anti-bacterial defense in fish.
16987670Our study provided further evidence for the existence of IL-21 in fish, and gained further insight into the immunological functions of IL-21 gene in fish.
17000687EXPERIMENTAL DESIGN: DNAs encoding cytokines that affect T cells [interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and the chemokine CCL21] and antigen-presenting cells [granulocyte macrophage colony-stimulating factor (GM-CSF)] were compared in mouse models as adjuvants to enhance CD8+ T-cell responses and tumor immunity.
17000687RESULTS: We found that (a) cytokine DNAs generally increased CD8+ T-cell responses against gp100; (b) ligation to Fc domains further enhanced T-cell responses; (c) adjuvant effects were sensitive to timing of DNA injection; (d) the most efficacious individual adjuvants for improving tumor-free survival were IL-12/Ig, IL-15/Ig, IL-21/Ig, GM-CSF/Ig, and CCL21; and (e) combinations of IL-2/Ig+IL-12/Ig, IL-2/Ig+IL-15/Ig, IL-12/Ig+IL-15/Ig, and IL-12/Ig+IL-21/Ig were most active; and (f) increased adjuvanticity of cytokine/Ig fusion DNAs was not related to higher tissue levels or greater stability.
17009101PURPOSE: To describe the pharmacodynamic effects of recombinant human interleukin-21 (IL-21) on core body temperature in cynomolgus monkeys using basic mechanisms of heat regulation.
17009101RESULTS: The effects of IL-21 were on the set-point and the circadian rhythm of metabolism.
17009101The model was able to describe a complex set of IL-21 induced phenomena, including 1) disappearance of the circadian rhythm, 2) no effect after first dose, and 3) high variability after second dose.
17009101CONCLUSIONS: The IL-21 induced effects on thermoregulation in cynomolgus monkeys are explained by a biologically plausible model.
17015709Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21.
17015709Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed.
17015709Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells.
17015709Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells.
17015709Therefore, IL-21 is a powerful growth factor for naive B cells.
17015709Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3.
17015709We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients.
17015709Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus.
17015709Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.
17050196The interleukin 21 (IL-21) receptor is expressed on T-cells, B-cells, and natural killer cells, and IL-21 is critical for regulating immunoglobulin production in vivo in cooperation with IL-4.
17050196So far, however, little is known about a role for IL-21 outside the immune system.
17050196We investigated the effect of IL-21 on hematopoiesis in vivo by using the hydrodynamics gene-delivery method.
17050196Overexpression of IL-21 increases Sca-1+ cells in the periphery and spleen.
17050196We found that even in RAG2-/- mice, which lack mature T-cells and B-cells, IL-21 induced an increase in KSL cells and CFU-GM in the spleen.
17050196These results demonstrate that IL-21 can induce the expansion of hematopoietic progenitor cells in vivo, even in the absence of mature T-cells and B-cells.
17077326The molecular signature of ALK- ALCL included overexpression of CCR7, CNTFR, IL22, and IL21 genes but did not provide any obvious clues to the molecular mechanism underlying this tumor subtype.
17077330IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo.
17077330Interleukin 21 (IL-21) is a member of the common gamma-chain family of cytokines, which influence a broad spectrum of immunologic responses.
17077330IL-21, but its specific role in Th1/Th2-cell differentiation and related effector responses remains to be clarified.
17077330Overall, our data show IL-21 plays a crucial role in supporting polarized Th2 responses in vivo, while appearing superfluous for Th1 and Th17 responses.
17083198Interleukin 21 (IL-21) is a novel type I cytokine that is significantly homologous to IL-2, IL-4 and IL-15.
17083198IL-21 is capable of co-stimulating mature T cells, B cells, NK cells, and of stimulating CD16 expression on the surface of NK cells to induce ADCC in innate immune response.
17083198Thus, IL-21 is a potential useful therapeutic molecule for immunotherapy of malignancies, by eliciting innate and adaptive anti-tumor responses in tumor-bearing hosts.
17097329Importantly, in experimental mice, synergistic anti-tumor effects have been observed with a combination treatment of agonistic mAb against DR5 together with either IL-21 or agonistic mAbs against CD40 and CD137.
17114505As IL-22 has also been shown to modulate cell cycle and proliferation mediators such as ERK1/2 and JNK, we studied the role of IL-22 in proliferation, apoptosis, and cell cycle regulation in EMT6 murine breast cancer cells in vitro and in vivo.
17114505Importantly, IL-22 exposure of EMT6 cells resulted in decreased levels of phosphorylated ERK1/2 and AKT protein kinases, indicating an inhibitory effect of IL-22 on signaling pathways promoting cell proliferation.
17126530Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8(+) T lymphocytes.
17126530IL-15 alone does not stimulate proliferation of naïve CD8 T cells, but can synergize with IL-21 to induce proliferation, suggesting a potential role for IL-21 in the defective homeostasis of CD8(+) T lymphocytes in SOCS1(-/-) mice.
17126530Since IL-21 strongly induced SOCS1 mRNA in CD8(+) T cells, we investigated whether SOCS1 regulates their response to IL-21.
17126530CD8(+) T cells isolated from SOCS1-deficient mice proliferated vigorously in response to IL-21+IL-15.
17126530In CD8(+) T lymphocytes expressing transgenic TCR, IL-21+IL-7 provided a stronger stimulus to naïve cells whereas IL-15+IL-21 potently stimulated memory cells.
17126530Compared to truly naïve or memory cells, SOCS1(-/-) H-Y TCR(+) CD8(+) T cells displayed CD44(lo)Ly6C(hi)CD122(int)CD127(lo) partial memory phenotype and exhibited stronger response to IL-15+IL-21 than truly naïve cells.
17126530In SOCS1(-/-) CD8(+) T cells, IL-21 caused greater reduction in IL-15 threshold for activation in a dose-dependent manner.
17126530SOCS1 deficiency did not modulate IL-21Ralpha expression or sensitivity to IL-21, but delayed the loss of IL-21-induced phospho-STAT3 signal.
17126530These results show that SOCS1 is a critical regulator of IL-21 signaling in CD8(+) T cells, and support the notion that sustained IL-21 signaling might also contribute to the aberrant T cell homeostasis in SOCS1-deficient mice.
17142735Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells.
17142735IL-21 is a recently identified type I cytokine, mainly produced by activated CD4(+) T cells.
17142735The objective of our study was to describe cellular intermediates that exist during IL-21-induced transition from an activated B cell to an Ig-secreting cell and to identify molecular mechanisms involved in this process.
17142735Novel Epstein-Barr Virus-positive human B cell lines with phenotypes characteristic of Ag-activated IgG(+) B cell blasts were used as a model system to study IL-21 effects in vitro.
17142735We show that IL-21 increased both proliferation and survival of B cell lines during the first 3 days of in vitro culture.
17142735Continued culture with IL-21 resulted in accumulation of cells in G(0)/G(1) stage of the cell cycle and increased apoptosis.
17142735Partial inhibition of IL-21-induced JAK/STAT signaling by the low-dose pharmacological agent, JAK inhibitor I, did not prevent the initial increase in proliferation.
17142735Our study is the first to show the link between IL-21-induced JAK/STAT signaling, c-Myc regulation, and differentiation of human B cells.
17234735The molecular basis of IL-21-mediated proliferation.
17234735Interleukin-21 (IL-21) is a type I cytokine that modulates functions of T, B, natural killer (NK), and myeloid cells.
17234735The IL-21 receptor (IL-21R) is closely related to the IL-2 receptor beta chain and is capable of transducing signals through its dimerization with the common cytokine receptor gamma chain (gamma(c)), the protein whose expression is defective in humans with X-linked severe combined immunodeficiency.
17234735To clarify the molecular basis of IL-21 actions, we investigated the role of tyrosine residues in the IL-21R cytoplasmic domain.
17234735Simultaneous mutation of all 6 tyrosines greatly diminished IL-21-mediated proliferation, whereas retention of tyrosine 510 (Y510) allowed full proliferation.
17234735Y510 efficiently mediated IL-21-induced phosphorylation of Stat1 and Stat3, but not of Stat5, and CD8(+) T cells from Stat1/Stat3 double knock-out mice exhibited decreased proliferation in response to IL-21 + IL-15.
17234735In addition, IL-21 weakly induced phosphorylation of Shc and Akt, and consistent with this, specific inhibitors of the MAPK and PI3K pathways inhibited IL-21-mediated proliferation.
17234735Collectively, these data indicate the involvement of the Jak-STAT, MAPK, and PI3K pathways in IL-21 signaling.
17241869The IL-21 receptor (IL-21R) is expressed by immune and nonimmune cells, raising the possibility that IL-21 has broad effects in gut inflammation.
17241869Intestinal epithelial cells were stimulated with IL-21, and cell-free supernatants were evaluated by a protein array and enzyme-linked immunosorbent assay.
17241869The effect of IL-21-treated epithelial cell supernatants on blood lymphocyte migration was assessed using a chemotaxis assay.
17241869Finally, we evaluated the effect of a neutralizing IL-21 antibody on MIP-3alpha synthesis in ex vivo organ cultures of IBD mucosal explants.
17241869Stimulation of intestinal epithelial cells with IL-21 resulted in enhanced phosphorylation of ERK1/2 and p38 and increased synthesis of macrophage inflammatory protein-3 alpha (MIP-3alpha), a T-cell chemoattractant.
17241869Inhibition of ERK1/2 but not p38 suppressed IL-21-induced MIP-3alpha production.
17241869IL-21-treated cell culture supernatants enhanced in vitro lymphocyte migration, and this effect was inhibited by anti-MIP-3alpha antibody.
17241869Treatment of IBD explants with anti-IL-21 reduced MIP-3alpha production.
17241869CONCLUSIONS: These data show that intestinal epithelial cells are a target of IL-21 and that IL-21 is involved in the cross-talk between epithelial and immune cells in the gut.
17255288Optimal therapeutic responses to the transfer of immune cells were associated with the cyclophosphamide-mediated induction of a "cytokine storm" [including granulocyte macrophage colony-stimulating factor, interleukin (IL)-1beta, IL-7, IL-15, IL-2, IL-21, and IFN-gamma], occurring during the "rebound phase" after drug-induced lymphodepletion.
17285290In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic tumor models and its effect on the density of tumor infiltrating T cells.
17285290IL-21 protein therapy and subsequently scored the densities of tumor infiltrating CD4(+) and CD8(+) T cells by immunohistochemistry.
17285290Whereas both routes of IL-21 administration significantly inhibited growth of small, established RenCa and B16 tumors, only s.
17285290We found a greater bioavailability and significant drainage of IL-21 to regional lymph nodes following s.
17285290In accordance, both routes of IL-21 administration significantly increased the density of tumor infiltrating CD8(+) T cells in both B16 and RenCa tumors; and in the RenCa model s.
17285290IL-21 led to a significantly higher density of tumor infiltrating CD8(+) T cells compared to i.
17285290The densities of CD4(+) T cells were unchanged following IL-21 treatments.
17285290Taken together, these data demonstrate that IL-21 protein has anti-tumor activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating CD8(+) T cells.
17289547Most notably, IL-1, tumor necrosis factor (TNF)-alpha, IL-6, IL-15, IL-17, IL-18, IL-21, IL-25, IL-25, IL-31 and IL-32 contribute in concert to pathophysiological events.
17312126IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production.
17312126The common gamma-chain cytokine, IL-21, is produced by CD4(+) T cells and mediates potent effects on a variety of immune cells including NK, T, and B cells.
17312126NKT cells express the receptor for IL-21; however, the effect of this cytokine on NKT cell function has not been studied.
17312126We show that IL-21 on its own enhances survival of NKT cells in vitro, and IL-21 increases the proliferation of NKT cells in combination with IL-2 or IL-15, and particularly with the CD1d-restricted glycosphingolipid Ag alpha-galactosylceramide.
17312126Similar to its effects on NK cells, IL-21 enhances NKT cell granular morphology, including granzyme B expression, and some inhibitory NK receptors, including Ly49C/I and CD94.
17312126IL-21 also enhanced NKT cell cytokine production in response to anti-CD3/CD28 in vitro.
17312126Furthermore, NKT cells may be subject to autocrine IL-21-mediated stimulation because they are potent producers of this cytokine following in vitro stimulation via CD3 and CD28, particularly in conjunction with IL-12 or following in vivo stimulation with alpha-galactosylceramide.
17312126Indeed, NKT cells produced much higher levels of IL-21 than conventional CD4 T cells in this assay.
17312126This study demonstrates that NKT cells are potentially a major source of IL-21, and that IL-21 may be an important factor in NKT cell-mediated immune regulation, both in its effects on NK, T, and B cells, as well as direct effects on NKT cells themselves.
17312126The influence of IL-21 in NKT cell-dependent models of tumor rejection, microbial clearance, autoimmunity, and allergy should be the subject of future investigations.
17319491Interestingly not only IL-2 but also IL-4, IL-7, IL-9, IL-15 and IL-21 utilize the gamma chain as an essential component of each receptors.
17319491The dysfunctions in IL-7- and IL-15-induced signal transduction cause the T cell and NK cell defect, respectively and dysfunctions in both IL-4- and IL-21-induced signal transduction cause the B cell dysfunction in X-SCID patients.
17319491IL-21 is a recently identified cytokine, which shares the gammac.
17319491IL-21 regulates the proliferation of T cells, the proliferation and differentiation of B cells, and the activation and expansion of NK cells.
17319491We demonstrated that human IL-21 was produced from activated CD4+ central and effector memory T cells but not from naive CD4+ T cells nor CD8+ T cells.
17319491Furthermore we found that IL-21 supported cytokine-driven proliferation of CD4+ helper T cells cooperatively with IL-7 and IL-15.
17352690Interleukin-21 (IL-21) is a newly described cytokine, produced by activated CD4+ T cells.
17352690Since the discovery in 2000, IL-21 has been the object of intensive research because of its homology to IL-2, IL-4 and IL-15, and its ability to modulate both innate and adaptive immune responses.
17352690IL-21 mediates its functions through a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R) and the common gamma-chain, that is shared with IL-2, IL-4, IL-7, IL-9, IL-13, and IL-15 receptors.
17352690IL-21R is originally described on T, B and NK cells, which is in accordance with the cell types that mostly respond to IL-21.
17352690Indeed, IL-21 augments the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and terminally differentiated plasma cells, and moreover, enhances the activity of natural killer cells.
17352690More recently, IL-21R has also been documented on non-immune cells, raising the possibility that IL-21 is an important mediator in the cross-talk between immune and non-immune cells.
17352690As discussed in this review, the potential role of IL-21 in immune-mediated and allergic diseases would seem to suggest that either disrupting or enhancing IL-21 signaling may be useful in specific clinical settings.
17447063Role of IL-21 in immune-regulation and tumor immunotherapy.
17447063IL-21, the most recently discovered member of the IL-2 cytokine family, is an attractive subject for research due to its involvement in experimental models of autoimmunity, its ability to down-regulate IgE production, and its anti-tumor properties.
17447063IL-21's functional activities partially overlap those of IL-2.
17447063Besides its activities on normal lymphoid cells, IL-21 is an in vitro growth factor for myeloma and acute-T cell leukemia cells, whereas it induces the apoptosis of B-CLL (chronic lymphocytic leukemia) cells.
17447063These findings indicate that the IL-21/IL-21R system exerts opposite functions in different lymphoid neoplasias, and suggest its employment in B-CLL therapy.
17447063Since IL-2, but not IL-21, is specifically required for the development of regulatory T (Treg) cell immune-suppressive functions, IL-21 may be a new tool for cancer immunotherapy.
17447063The preliminary data from phase-I clinical studies suggest that the use of IL-21 is feasible and may result in immune-enhancing effects.
17462506Idd3, has also been mapped to the interval containing the murine gene for IL-21 (Il21), making Il21 and the human orthologue IL21 a functional and positional candidate gene for type 1 diabetes.
17462506To investigate the contribution of the human genes for IL-21 and its receptor (IL-21R) to susceptibility to type 1 diabetes, we re-sequenced IL21 to identify novel sequence variants, searched for informative variants of IL21R, and studied the association of these variants with the disease.
17462506These data suggest a contribution of IL21 and IL21R to genetic susceptibility to type 1 diabetes and possible involvement of IL-21 and its receptor system in the disease pathogenesis.
17469116Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
17469116OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment.
17469116Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations.
17469116Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies.
17469116In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations.
17469116RESULTS: All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43.
17469116Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43.
17469116Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations.
17509926Structurally, IL-21 shows homology to IL-2, IL-4, and IL-15 proteins.
17509926IL-21 shares the common gamma-chain with the other three cytokines but, in addition, binds to a unique IL-21Ralpha chain, and activates the JAK/STAT pathway.
17509926IL-21 is mainly produced by activated T-cells but targets a broad range of lymphoid and myeloid cells of the immune system and therefore is able to regulate innate and acquired immune responses.
17509926This review intends to give the reader an overview of the recent findings concerning the biology of IL-21 and its physiological role in immunity, infection, and cancer.
17510323To investigate the mechanisms underlying such increased turnover, we compared BM, lymph nodes, and spleen CD8 cells from untreated C57BL/6 mice regarding in vivo proliferation within the organ; in vitro response to interleukin-7 (IL-7), IL-15, IL-21; ex vivo expression of membrane CD127 (IL-7Ralpha), intracellular Bcl-2, phospho-STAT-5 (signal transducer and activator of transcription 5), phospho-p38 mitogen activated protein kinase (MAPK); and in vivo proliferation on adoptive transfer.
17510323In contrast, purified CD8(+) cells from the BM did not show an enhanced in vitro proliferative response to IL-7, IL-15, and IL-21 compared with corresponding spleen cells.
17516151Interleukin-21 (IL-21) is a novel cytokine that is currently under clinical investigations as a potential anti-cancer agent.
17516151Like many other anti-cancer agents, including other interleukins, IL-21 is seen to produce a broad range of biological effects that may be related to both efficacy and safety of treatment.
17516151The present analysis investigates the observed pharmacodynamics effects on red blood cells following various treatment schedules of human IL-21 administrated to cynomolgus monkeys.
17516151In conclusion, the model describes the IL-21 induced drop in red blood cells to be (1) caused by removal rather than suppression of production, consistent with increased reticulocyte concentration, and (2) considerably delayed compared to dosing, i.
17530391The activatory NK receptors were not induced significantly after treatment with IL-12, IL-18, and IL-21 for 48 h.
17543992Our findings show that there is no mislocalization of TDP-43 to the cytoplasm in motor neurons of mutant SOD1 transgenic mice, nor association of TDP-43 with ubiquitinated inclusions.
17543992In contrast, mislocalization of TDP-43 to the cytoplasm and association with ubiquitinated inclusions was found in the ALS cases, including those carrying mutations in SOD1.
17543992Interestingly, there was no association of TDP-43 with ubiquitinated hyaline conglomerate inclusions, pathology closely associated with ALS cases carrying mutations in SOD1.
17543992Our findings indicate that the process of motor neuron degeneration in mutant SOD1 transgenic mice is unlikely to involve the abnormalities of TDP-43 described in the human disease.
17565322MATERIALS: To explore the actions of IL-21 with other gammac-dependent cytokines in alloreactivity, mRNA expression of IL-21, IL-21R alpha-chain, and IL-2 proliferation and cytotoxicity was measured after stimulation in mixed lymphocyte reactions.
17565322Additionally, IL-21 and IL-21R alpha-chain expression was studied in biopsies of heart transplant patients.
17565322RESULTS: Analysis of mRNA expression levels of allostimulated T-cells showed a 10-fold induction of IL-21 and IL-21R alpha-chain.
17565322Interestingly, induction of IL-21 was highly dependent on IL-2 (as in the presence of anti-IL-2, anti-IL-2R alpha-chain, and the immunosuppressive drugs cyclosporine A, tacrolimus, and rapamycin) the transcription of IL-21 was almost completely inhibited, whereas in the presence of exogenous IL-2 the mRNA expression of IL-21 was even more upregulated.
17565322IL-21 functioned as a costimulator for IL-2 to augment proliferation and cytotoxic responses, while blockade of the IL-2 route abrogated these functions of IL-21.
17565322Blockade of the IL-21 route by anti-IL-21R alpha-chain monoclonal antibodies inhibited the proliferation of alloactivated T-cells.
17565322Also, in vivo alloreactivity was associated with IL-21/IL-21R alpha-chain expression.
17565322After heart transplantation, the highest intragraft IL-21, IL-21R alpha-chain, and IL-2 mRNA expression levels were measured during acute rejection (P<0.
17565322CONCLUSION: IL-21 is a critical cytokine for IL-2 dependent immune processes.
17565322Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.
17569066Except for rare familial forms of ALS associated with mutations in superoxide dismutase type 1 (SOD1), which are associated with neuronal inclusions that contain SOD1, specific molecular or cellular markers that differentiate ALS from other motor neuron disorders have not been available.
17569066The results suggest that TDP-43 immunoreactivity is useful in differentiating FTLD-MND and ALS from other disorders associated with upper or lower motor neuron pathology.
17574601The recently discovered interleukin-21 (IL-21) shows strong tumor attenuation in preclinical studies, and is considered a promising cancer immunotherapy agent.
17574601IL-21-antitumor effects provided the basis for application of the optimization methodology, aimed at finding improved immunotherapeutic regimens.
17574601Both dosages and inter-dosing intervals were optimized while considering maximal efficacy, determined by reduction of tumor burden, and minimal toxicity, estimated by cumulative IL-21 doses applied.
17574601Collectively, administration times shifted towards treatment onset, and IL-21 intensities sequentially decreased.
17574601Interestingly, there was a certain window in which deviations in the total IL-21 dosage administered largely influenced tumor elimination.
17574601Our work provides initial basis for identifying clinically applicable IL-21 therapeutic strategies with improved efficacy/toxicity ratios.
17620425RSV-F in combination with adenovirus vectors encoding interleukin (IL)-2, IL-12, IL-18, IL-21, or granulocyte macrophage colony-stimulating factor significantly enhanced the antitumor effect on the directly vector-treated tumor and also on the contralateral tumor.
17620425Intratumoral coexpression of RSV-F and IL-21 resulted in the highest tumor growth inhibition and improved survival.
17624663High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma.
17624663We surveyed IL-21 receptor (IL-21R) in leukemia and lymphoma and found that follicular lymphoma cells showed exceptionally high IL-21R expression.
17624663Notably, IL-21 showed divergent effects depending on the cell origin: growth stimulation in Burkitt lymphoma cell lines and adult T cell leukemia/lymphoma cell lines but induction of apoptosis in B lymphoma cell lines with t(14;18)(q32;q21), a marker karyotype of follicular lymphoma.
17624663IL-21 activated caspase-8 and -3 and reduced mitochondrial membrane potential.
17624663More importantly, IL-21 decreased Bcl-2 expression but increased Bax expression.
17624663These results support a new therapeutic approach using the IL-21/IL-21R system in follicular lymphoma.
17635612Interleukin-21 (IL-21) is a cytokine with pleiotropic effects on various cell types including dendritic cells, B cells, T cells and natural killer (NK) cells.
17635612To evaluate if IL-21 affects human NK cell subpopulations in a similar fashion, functional studies were performed on CD56(dim) and CD56(bright) NK cells, both bearing IL-21 receptors at identical densities.
17635612Stimulation with IL-21 strongly induced proliferation of CD56(bright) NK cells and cytotoxicity against K562 target cells was preferentially augmented in CD56(dim) NK cells.
17635612In contrast, stimulation with IL-2 and IL-21 alone or in combination failed to induce interferon-gamma and tumour necrosis factor-alpha production in the two NK cell subsets.
17635612Intracellular analysis of signal transducer and activator of transcription (STAT) proteins revealed that IL-21 by itself induces phosphorylation of STAT1 and STAT3 in CD56(dim) NK cells, and to an even higher degree in CD56(bright) NK cells.
17635612In contrast, STAT5 was strongly phosphorylated only in CD56(bright) NK cells by low-dose IL-2, while IL-21 did not affect STAT5 at all.
17635612In summary, we present data indicating that the NK-cell-directed cytokines IL-2 and IL-21 not only affect functions in NK cell subpopulations differently but can also act additively.
17673207Interleukin-21 (IL-21) has pleiotropic functions on the cells, which play roles in both innate and acquired immunity, such as T cells, B cells, natural killer (NK) cells and dendritic cells.
17673207In this study we identified a novel isoform of IL-21, IL-21iso in human and mouse.
17673207IL-21iso might be an alternative splicing variant form and the C-terminal region of predicted IL-21iso amino acid sequences were different from original IL-21 in both human and mouse.
17673207In spite of the differences in C-terminal amino acid sequences, both human IL-21 and IL-21iso showed comparable proliferative effect on anti-CD40 Ab-activated primary B cells, anti-CD3 Ab-activated primary T cells and human NK cell line, NK0, and upregulated IFN-gamma production from NK0.
17673207Furthermore IL-21 and IL-21iso similarly activated STAT1 and STAT3.
17673207However, cycloheximide treatment partially blocked the upregulation of IL-21iso mRNA in activated T cells while little affected the IL-21 mRNA expression suggesting that de novo protein synthesis is required for the full expression of IL-21iso transcript.
17673207These results may suggest there are some different regulatory mechanisms to produce IL-21 or IL-21iso in transcriptional and secretory steps.
17678711IL-21 enhances dendritic cell ability to induce interferon-gamma production by natural killer T cells.
17678711However, the influence of IL-21 on dendritic cell (DC) activation of natural killer T (NKT) cells has not yet been elucidated.
17678711In the present study, we examined the effect of IL-21 on murine myeloid DC ability to induce NKT cell production of interferon-gamma (IFN-gamma) and IL-4.
17678711Pretreatment of DCs with IL-21 and alpha-galactosylceramide (alpha-GalCer), an NKT cell-specific ligand, resulted in the enhanced ability of the DCs to induce NKT cell production of IFN-gamma but not IL-4 in vitro compared to DCs pretreated with alpha-GalCer alone.
17678711IL-21 was observed when DCs pretreated with IL-21 and alpha-GalCer in vitro were transferred into naïve mice.
17678711Direct administration of IL-21 to the mice also enhanced IFN-gamma production after injection of alpha-GalCer.
17678711Thus, IL-21 can modify DC ability to selectively enhance NKT cell production of IFN-gamma upon stimulation with alpha-GalCer.
17683114Cytokines signaling through receptors sharing the common gamma chain (gamma(c)), including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, are critical for the generation and peripheral homeostasis of B, T and NK cells.
17695518UNLABELLED: We examined the effect of the combination of herpes simplex virus type1-thymidine kinase (HSV-TK)-suicide gene therapy and interleukin-21 (IL-21) immune gene therapy.
17695518Plasmid DNA containing HSV-TK-suicide gene or IL-21 gene was injected into TE2 and Colon26 tumors developed in nude mice and electric pulses were then delivered.
17695518IL-21-transduced tumors disappeared completely in syngeneic BALB/c mice.
17695518These data suggest that IL-21 induces T- and NK-cell-dependent antitumor effects.
17695518Furthermore, the growth of IL-21-producing tumors subsequently transduced with MKp-TK by electroporation was significantly retarded compared with control groups.
17695518CONCLUSION: Using the minimal promoter region of MK to drive the HSV-TK gene and in vivo electroporation to transduce IL-21 DNA into the tumors produced an efficient gene therapy with improved safety.
17695518To our knowledge, this is the first report of a combination gene therapy using HSV-TK/GCVand IL-21.
17698559Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4+ T cell subsets.
17698559IL-21 regulates certain functions of T cells, B cells, NK cells and dendritic cells.
17698559Although activated CD4(+) T cells produce IL-21, data identifying the specific CD4(+) T cell subsets that produce IL-21 are conflicting.
17698559In a previous study, mouse IL-21 message was detected in T(H)2, whereas human IL-21 (hIL-21) message was found in both T(H)1 and follicular helper T cells.
17698559To identify the IL-21-secreting cell populations in human, we established a hybridoma cell line producing an anti-hIL-21 mAb.
17698559Moreover, IL-21 was produced upon activation by some IFN-gamma-producing T(H)1-polarized cells and some IL-17-producing T(H)17-polarized cells, but not by IL-4-producing T(H)2-polarized cells.
17698559These results suggest that specific CD4(+) T cell populations produce IL-21.
17698559In the functional analysis, we found that IL-21 significantly enhanced the cytokine-driven proliferation of CD4(+) helper T cells synergistically with IL-7 and IL-15 without T cell activation stimuli.
17698559Taken together, IL-21 produced from CD4(+) memory T cells may have a supportive role in the maintenance of CD4(+) T cell subsets.
17707061PURPOSE: We evaluated the antitumor effects of IL-21 gene transfer into mouse RenCa renal cell carcinoma cells, so that cells could spontaneously secrete IL-21.
17707061MATERIALS AND METHODS: The IL-21 gene was introduced into RenCa cells by the liposome mediated method using Lipofectamine.
17707061The in vivo antitumor effect of IL-21 secreting RenCa cells was assessed by subcutaneous injection into syngeneic BALB/c mice.
17707061The cytotoxic activity of splenocytes in mice injected with IL-21 secreting RenCa cells was determined using the CytoTox 96 nonradioactive cytotoxicity assay.
17707061RESULTS: IL-21 secreting RenCa cells were almost all rejected following subcutaneous injection into syngeneic mice.
17707061The antitumor effect of IL-21 secreting RenCa cells remained in mice in which CD4 T cells had been depleted but it was totally abrogated in mice depleted of CD8 T cells or natural killer cells.
17707061Cytotoxic activities of splenocytes were higher in IL-21 secreting RenCa cell rejected mice than in parental RenCa mice.
17707061Immunohistochemical study also supported the involvement of CD8 T cells and natural killer cells in the antitumor effect of IL-21 secreting RenCa cells.
17707061Moreover, mitomycin C treated IL-21 secreting RenCa cells inhibited the growth of parental RenCa at distant site.
17707061CONCLUSIONS: IL-21 secreting RenCa could be rejected in syngeneic mice by the activation of CD8 T cells and natural killer cells.
17707061Moreover, mitomycin C treated IL-21 secreting RenCa cells could work as a tumor vaccine for parental RenCa.
17712836Accumulating evidence now suggests that interleukin-21 (IL-21), the newest member of the common gamma-chain-dependent cytokine family, is a key component of the inflammatory cascade.
17712836IL-21 is highly produced by activated CD4+ lymphocytes in the inflamed gut of patients with CD, where it contributes to sustaining the ongoing Th1 inflammation.
17712836IL-21 also increases the secretion of extracellular matrix-degrading enzymes by fibroblasts and of MIP-3alpha by epithelial cells.
17713571IL-21 enhances antitumor responses without stimulating proliferation of malignant T cells of patients with Sézary syndrome.
17713571IL-21, a common gamma-chain cytokine secreted by activated CD4+ T cells, influences both humoral and cell-mediated immune responses through the regulation of T, B, dendritic, and natural killer (NK) cells.
17713571As a modulator of both innate and adaptive immune responses, IL-21 could play an important role in augmenting cell-mediated immunity in these patients.
17713571Normal donor and Sézary syndrome patient peripheral blood mononuclear cells were cultured with IL-21 and tested for CD8+ T- and NK-cell activation, NK-cell cytotoxicity, and tumor cell proliferation and apoptosis.
17713571IL-21 resulted in a modest increase in CD8+ T- and NK-cell activation, associated with a marked increase in cytolytic activity against both K562 and malignant CD4+ T-cell targets.
17713571Although IL-21 failed to demonstrate pro-apoptotic effects on the malignant CD4+ T cells, it is noteworthy that it had no demonstrable proliferative effects on these cells.
17713571Thus, IL-21 may play an important role in enhancing the host immune response of Sézary syndrome patients through the increased cytolytic activity of T and NK cells.
17898044IL-21 synergizes with IL-7 to augment expansion and anti-tumor function of cytotoxic T cells.
17898044IL-21, a recently identified member of the common gamma-chain (gammac) receptor cytokine family, has been shown to be an important regulator of both innate and adaptive immune responses.
17898044In this study, we investigated whether IL-21 could synergize with another gammac cytokine, IL-7, to induce enhanced proliferation and effector function of tumor antigen-specific CD8(+) T cells.
17898044Our results showed that IL-21 could significantly augment the IL-7-induced expansion of cytotoxic T cells, possibly by preventing the cytokine-induced down-regulation of the IL-7Ralpha (CD127) on antigen-stimulated T cells.
17898044IL-21 also greatly enhanced the production of T(h)1 and inflammatory cytokines by activated T cells, including IFN-gamma, IL-2, tumor necrosis factor-alpha, granulocyte macrophage colony-stimulating factor, IL-1beta and IL-6.
17898044Finally, the addition of IL-21 to IL-7-cultured CTLs resulted in a considerably higher level of cytolytic activity, as measured by specific killing of tumor cells or antigen-pulsed target cells.
17898044These results suggest that IL-21 may play a cooperative role with IL-7 in modulating primary CD8(+) T-cell responses and may have important implications for immunotherapy of cancer.
17911475Interleukin-21 (IL-21) is a pleiotropic cytokine whose function is only now being unraveled.
17911475Abundant evidence indicates that activated CD4 T cells are the primary, if not the only, source of IL-21.
17911475While it is clear that IL-21 is actively transcribed by naïve activated T cells, recent studies have shown that IL-21 potentially promotes a developmental shift of naïve T cells toward the Th2 phenotype.
17911475Previous results indicate the elevation of IL-21 expression by BXSB-Yaa mice at an age when the early characteristics of autoimmune processes first become evident.
17911475We set out to determine whether IL-21 was necessary for disease progression in BXSB-Yaa mice.
17911475Mice were treated for 24 weeks with soluble IL-21R-Fc in order to therapeutically neutralize the IL-21 present.
17911475The results overall suggest a biphasic effect of IL-21, negatively influencing survival early on and positively influencing survival at later stages.
17911475We propose that IL-21 exerts a pleiotropic effect in which it promotes the protective effects of CD8+ suppressor cells in the early disease phase and then promotes the humoral components of SLE in the later disease stages.
17911475This experiment provides preliminary evidence for a role of IL-21 in modulating the severity of SLE in BXSB-Yaa mice.
17938255The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways.
17938255Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common gamma chain and of its JAK3-associated pathway.
17938255IL-21 failed to induce CLL cell proliferation and instead promoted apoptosis.
17938255Following cell exposure to IL-15, phosphorylation of STAT5 was predominantly observed, whereas, following stimulation with IL-21, there was predominant STAT1 and STAT3 activation.
17938255Moreover, IL-15 but not IL-21 caused an increased phosphorylation of Shc and ERK1/2.
17942669Murine Th17 cells differentiate from naïve T cell precursors in the presence of TGF-beta and IL-6 or IL-21.
17942669IL-6 and IL-21 were unable to induce IL-17 expression in either naïve or effector T cells, and TGF-beta actually inhibited IL-17 expression.
17947662Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration.
17947662Previously, we reported that costimulation of purified human B cells with IL-21 and anti-CD40 resulted in efficient PC differentiation.
17947662In this study, we addressed whether de novo production of IL-21 was involved in direct T cell-induced B cell activation, proliferation, and PC differentiation.
17947662We found that activated human peripheral blood CD4(+) T cells expressed mRNA for a number of cytokines, including IL-21, which was confirmed at the protein level.
17947662Strikingly, neutralization of IL-21 with an IL-21R fusion protein (IL-21R-Fc) significantly inhibited T cell-induced B cell activation, proliferation, PC differentiation, and Ig production.
17947662Importantly, IL-21 was found to be involved in PC differentiation from both naive and memory B cells.
17947662These data are the first to document that B cell activation, expansion, and PC differentiation induced by direct interaction of B cells with activated T cells requires IL-21.
17953510Interleukin-21 (IL-21), a potent immunomodulatory four-alpha-helical-bundle type I cytokine, is produced by NKT and CD4(+) T cells and has pleiotropic effects on both innate and adaptive immune responses.
17953510Conversely, IL-21 also has direct inhibitory effects on the antigen-presenting function of dendritic cells and can be proapoptotic for B cells and NK cells.
17953510IL-21 is also produced by Th17 cells and is a critical regulator of Th17 development.
17953510The regulatory activity of IL-21 is modulated by the differentiation state of its target cells as well as by other cytokines or costimulatory molecules.
17953510IL-21 has potent antitumor activity but is also associated with the development of autoimmune disease.
17953510IL-21 transcription is dependent on a calcium signal and NFAT sites, and IL-21 requires Stat3 for its signaling.
17953510The key to harnessing the power of IL-21 will depend on better understanding its range of biological actions, its mechanism of action, and the molecular basis of regulation of expression of IL-21 and its receptor.
17962339EXPERIMENTAL DESIGN: Human NK cells stimulated with cetuximab-coated tumor cells and interleukin-2 (IL-2), IL-12, or IL-21 were assessed for ADCC and secretion of IFN-gamma and T cell-recruiting chemokines.
17962339IL-21 and cetuximab were given to nude mice bearing HER1-positive xenografts.
17962339RESULTS: Stimulation of human NK cells with cetuximab-coated tumor cells and IL-2, IL-12, or IL-21 resulted in 3-fold to 10-fold higher IFN-gamma production than was observed with either agent alone.
17962339IL-2, IL-12, and IL-21 enhanced NK cell ADCC against tumor cells treated with cetuximab.
17962339The combination of cetuximab, trastuzumab (an anti-HER2 monoclonal antibody), and IL-21 mediated greater NK cell cytokine secretion and ADCC than any agent alone.
17962339Furthermore, administration of IL-21 enhanced the effects of cetuximab in a murine tumor model.
17982568Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, is mainly produced by activated T lymphocytes, particularly the inflammatory Th17 subset, and is believed to be a key factor in the transition between innate and acquired immunity.
17982568In addition, it was demonstrated that IL-21 is a potent antitumor agent, making it a promising candidate for the development of therapeutic tools.
17982568IL-21 has also been associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.
17982568This review will summarize the biological functions of IL-21 and its potential role in inflammation.
17996992Antigenic stimulation of peripheral blood CD4+ T cells from BCG-vaccinated cattle enhanced expression of perforin and IFNgamma in cells expressing a CD45RA-CD45RO+CD62L+ cell surface phenotype, enhanced transcription of granulysin, IFNgamma, perforin, IL-4, IL-13, and IL-21, and enhanced anti-mycobacterial activity of CD4+ T cells against BCG-infected macrophages.
18039580In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26.
18053164The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors.
18053164Our data indicate that the addition of IL-21 has a synergistic effect by increasing the numbers of NK cells on a large scale.
18053164The addition of IL-21 to IL-15 or IL-2 can modify the pattern of the KIR receptors and inhibit NKp44 expression by reducing the expression of the adaptor DAP-12.
18053164IL-21 also preserved the production of interferon-gamma and enhanced the cytotoxic properties of NK cells.
18053164Our findings indicate that the proinflammatory cytokines IL-2, IL-15 and IL-21 can modify the peripheral repertoire of NK cells.
18056166Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines.
18056166IL-21 has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells.
18056166Functionally, these activities promote immune responses and point to a physiologic role of IL-21 in autoimmunity and immune enhancement.
18056166Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease.
18056166Recently conducted phase 1 trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.
18056403IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice.
18056403The anaphylactic reaction was completely abolished by the administration of recombinant mouse IL-21 or an IL-21 expression plasmid in terms of the change of body temperature and anaphylactic symptoms.
18056403Moreover, mice genetically deficient for Id2 were completely unsusceptible to IL-21-induced prevention of IgE CSR and anaphylaxis.
18056403The present study strongly suggests that IL-21 is capable of regulating systemic allergic reactions by inducing the transcriptional regulator Id2, and the cytokine may be useful for clinical intervention for allergic diseases including anaphylaxis.
18172584Designated Th17 cells, this lineage selectively produces proinflammatory cytokines including IL-17, IL-21, and IL-22.
18182577IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro.
18182577Interleukin-21 (IL-21) is a recently identified gamma-chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system.
18182577Based on this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune-mediated clearance of the chronic lymphocytic leukemia (CLL) cells.
18182577IL-21-induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA prevented IL-21-induced apoptosis.
18182577IL-21 treatment of CLL cells but not normal T cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies.
18182577In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody-dependent cellular cytotoxicity against rituximab-coated CLL cells in vitro.
18182577These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic end point to measure biologic effect of this cytokine in vivo.
18190607IL-21 activates lymphoid T and B cells, modulates antibody production but also suppresses maturation of myeloid dendritic cells; however, its role in the differentiation and function of other myeloid cells remains less clear.
18190607In this study we analysed IL-21/IL-21Ralpha effects on macrophage (MPhi) differentiation and function.
18190607MPhi could be generated readily from bone marrow with MPhi-colony-stimulating factor in the presence of IL-21 (designated IL-21MPhi) or from IL-21Ralpha-/- mice.
18190607IL-21Ralpha-/- mice had normal MPhi numbers, suggesting a non-essential role of both IL-21 and the IL-21Ralpha for MPhi generation.
18190607However, short-term IL-21 stimulation did not enhance MPhi proliferation but induced anti-apoptotic cell-cycle regulators p21(waf1)/p27(Kip1) and expression of suppressors of cytokine signalling (SOCS)2/SOCS3.
18190607Moreover, IL-21 enhanced phagocytosis by MPhi via IL-21Ralpha signalling and supports protease activity and matrix metalloproteinase 12 expression.
18190607Stimulating MPhi with IL-21 enhanced their capacity to induce antigen-specific CD4+ T cell proliferation in dependence from the IL-21Ralpha, which was not the case for CD8+ T cells.
18190607Taken together, IL-21 plays a previously unrecognized role in modulating innate and acquired effector mechanisms of murine MPhi by linking these different functions to support CD4+ T cell-mediated immune responses.
18220949Interleukin-21 (IL-21) controls inflammatory pathways in the gut.
18220949Interleukin-21 (IL-21), the latest member of the common gamma-chain-dependent cytokine family, is a product of activated CD4+ T cells and natural killer T cells.
18220949IL-21 is produced in excess in CD tissue, where it helps sustain the ongoing Th1 inflammation.
18220949High IL-21 production occurs also in the inflamed colon of most patients with UC, a disease that is not associated with a marked Th1 cell response.
18220949This suggests that, in the gut, IL-21 can modulate additional inflammatory pathways other than enhancing Th1 cell immunity.
18220949Indeed, IL-21 stimulates the secretion of extracellular matrix degrading enzymes by fibroblasts, and of the T cell chemoattractant, MIP-3 alpha, by epithelial cells.
18222514We have recently described novel type III latency EBV+ B cell lines (OCI-BCLs) that were induced to differentiate into late plasmablasts/early plasma cells in culture with interleukin-21 (IL-21), mimicking normal B cell development.
18222514The objective of this study was to determine whether IL-21-mediated signals also regulate the expression of key EBV latent proteins during this window of development.
18222514Here we show that IL-21-reduced gene and protein expression of growth-transforming EBV nuclear antigen 2 (EBNA2) in OCI-BCLs.
18222514The effect of IL-21 on EBNA2 and LMP1 expression was attenuated by a pharmacological JAK inhibitor indicating involvement of JAK/STAT signalling in this process.
18281483Whereas both IL-2 and IL-15 modulated, in a CTCL cell line, the expression of >1,000 gene transcripts by at least 2-fold, IL-21 up-regulated <40 genes.
18281483In contrast, IL-21 selectively activated signal transducers and activators of transcription 3.
18281483These findings document the vastly different effect of IL-2 and IL-15 versus IL-21 on CTCL cells.
18281483They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells.
18286285IL-21 induces in vivo immune activation of NK cells and CD8(+) T cells in patients with metastatic melanoma and renal cell carcinoma.
18286285PURPOSE: Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers.
18286285Here we report the effects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine.
18286285RESULTS: Effects of IL-21 were observed at all dose levels.
18286285In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods.
18286285Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo.
18286285CONCLUSIONS: IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8(+) T cell activation.
18292497We now show that VIP with TGFbeta stimulates the transformation of CD4 T cells to a distinctive type of Th17 cell that generates IL-17 but not IL-6 or IL-21.
18292497Compared with Th17 cells elicited by IL-6, those evoked by VIP were similar in the secretion of IL-17 and IL-22, but lacked IL-21 secretion.
18292499As reported previously, IL-21 efficiently induced the differentiation of activated human CD19+ B cells into IgD-CD38+ plasma cells in vitro.
18296629IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis.
18296629Here, we show that both the interleukin (IL)-21 receptor as well as IL-21 are expressed by HL cells.
18296629IL-21 activates signal transducer of activation and transcription 3 (STAT3) and STAT5 in HL cell lines and activated human B cells.
18299268Interleukin-21 (IL-21) is a newly described, typical, four-helix cytokine showing significant homology with IL-2, IL-4 and IL-15.
18299268Plasma IL-21 levels correlated with IgG1 and IgG3 levels.
18299268Additionally, plasma IL-21 levels correlated with hemoglobin levels in younger children and with parasite density.
18299268Here we describe the relationship between IL-21 and antibodies for erythrocyte-binding antigen-175 (EBA-175) peptide 4, a malaria vaccine candidate in Gabonese children with acute falciparum malaria.
18300037In this experiment, the gene of IL-21 was firstly amplified from plasmid pcDNA3.
18300037IL21 by PCR and cloned into the plasmid pRSC, forming recombinant plasmid pRSC-IL21.
18300037It was identified by the analysis of endonuclease digestion, DNA sequencing, the IL-21 and Ag85A expression in SP2/0 cells.
18300037The results showed that the DNA vaccine constructs pRSC-IL21-Ag85A was successfully constructed since the Ag85A and IL-21 was correctly expressed in SP2/0 cells respectively, and it elicited stronger immune responses in Balb/c mice than that of mice immunized with pRSC-Ag85A and the efficiency was as BCG did.
18324400AIM: IL-21 is the most recently identified member of the IL-2 cytokine family.
18324400Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model.
18324400MATERIALS AND METHODS: Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings.
18324400RESULTS: When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response.
18324400More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs.
18324400The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33%, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect.
18324400CONCLUSIONS: Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.
18368049At low concentrations, TGF-beta synergizes with interleukin (IL)-6 and IL-21 (refs 9-11) to promote IL-23 receptor (Il23r) expression, favouring T(H)17 cell differentiation.
18368049IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORgammat, thereby promoting T(H)17 cell differentiation.
18388517Accumulating evidence indicates that other cytokines, including IL-15, IL-18, and IL-21 may also play an important role in rheumatoid arthritis.
18395085We here examined whether IL-21 is necessary for the initiation and progress of experimental colitis and whether it regulates specific pathways of inflammation.
18395085METHODS: Both dextran sulfate sodium colitis and trinitrobenzene sulfonic acid-relapsing colitis were induced in wild-type and IL-21-deficient mice.
18395085CD4(+)CD25(-) T cells from wild-type and IL-21-deficient mice were differentiated in T helper cell (Th)17-polarizing conditions, with or without IL-21 or an antagonistic IL-21R/Fc.
18395085We also examined whether blockade of IL-21 by anti-IL-21 antibody reduced IL-17 in cultures of IBD lamina propria CD3(+) T lymphocytes.
18395085RESULTS: High IL-21 was seen in wild-type mice with dextran sulfate sodium- and trinitrobenzene sulfonic acid-relapsing colitis.
18395085IL-21-deficient mice were largely protected against both colitides and were unable to up-regulate Th17-associated molecules during gut inflammation, thus suggesting a role for IL-21 in controlling Th17 cell responses.
18395085Indeed, naïve T cells from IL-21-deficient mice failed to differentiate into Th17 cells.
18395085Moreover, in the presence of transforming growth factor-beta1, exogenous IL-21 substituted for IL-6 in driving IL-17 induction.
18395085Neutralization of IL-21 reduced IL-17 secretion by IBD lamina propria lymphocytes.
18395085CONCLUSIONS: These results indicate that IL-21 is a critical regulator of inflammation and Th17 cell responses in the gut.
18396105TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.
18396105TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1.
18396105METHODS: TARDBP was sequenced in 259 patients with ALS, FTLD, or both.
18400188These cells are characterized as preferential producers of interleukin-17A (IL-17A), IL-17F, IL-21, and IL-22.
18413772Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15 that has antitumor activity alone in mouse experimental tumor models and a tolerable safety profile in phase I trials in patients with metastatic melanoma and renal cell carcinoma.
18413772Several monoclonal antibodies (mAb) targeted at tumor-associated antigens also have improved antitumor activities in mice when used in combination with IL-21.
18413772Herein, we show that sequentially combining TrimAb with recombinant IL-21 can significantly improve the antitumor activity of this combination against very advanced disease.
18413772These data further support the use of IL-21 in adjuvant settings where strong T cell-mediated immune responses to tumors can be generated.
18426663This study was purposed to investigate the proliferation and antitumor activity of rhG-CSF-mobilized peripheral blood mononuclear cells (G-PBMNCs) activated by interleukin 21 (IL-21) alone or in combination with interleukin 15 (IL-15)/interleukin 2 (IL-2) and to evaluate the feasibility and value of tumor immunotherapy with cytokine combinations.
18426663PBMNCs were activated by IL-21 alone or in combination with IL-15/IL-2 in vitro, and the proliferation of the activated G-PBMNCs was analyzed by CCK-8 assay.
18426663The results showed that the cytotoxicity of IL-21 group had no difference from which of IL-2 group.
18426663When G-PBMNCs were exposed to the combinations of IL21+IL15/IL21+IL15+IL2, the cytotoxicity was significantly enhanced at E:T ratio of 25:1, as compared with combination of IL21+IL2 (p<0.
18426663It is concluded that IL-21 alone enhance the antitumor activity of G-PBMNCs, which further strengthens when IL-21 combinated with IL-15.
18441505Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by selective motor neuron death.
18441505Although the mechanism of ALS is still unclear, there are many hypotheses concerning its cause, including loss of neurotrophic support to motor neurons.
18454150However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines.
18454151In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear receptor RORgammat.
18454151We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood.
18467657Interleukin-21 (IL-21) and its receptor represent the sixth cytokine system whose actions were recognized to require the common cytokine receptor gamma chain.
18467657IL-21 is produced by activated CD4+ T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lymphohematopoietic lineages.
18467657Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8+ T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells.
18467657Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent.
18467657The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease.
18469800IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
18469800Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4(+) T cells, TGF-beta and IL-21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2.
18474630Development and characterization of IL-21-producing CD4+ T cells.
18474630In this study, we investigated the differentiation and characteristics of IL-21-producing CD4(+) T cells by intracellular staining.
18474630We also found that IL-6 and -21 potently induced the development of IL-21-producing CD4(+) T cells without the induction of IL-4, IFN-gamma, IL-17A, or IL-17F production.
18474630On the other hand, TGF-beta inhibited IL-6- and IL-21-induced development of IL-21-producing CD4(+) T cells.
18474630IL-2 enhanced the development of IL-21-producing CD4(+) T cells under Th17-polarizing conditions.
18474630Finally, IL-21-producing CD4(+) T cells exhibited a stable phenotype of IL-21 production in the presence of IL-6, but retained the potential to produce IL-4 under Th2-polarizing conditions and IL-17A under Th17-polarizing conditions.
18474630These results suggest that IL-21-producing CD4(+) T cells exhibit distinct characteristics from Th17 cells and develop preferentially in an IL-6-rich environment devoid of TGF-beta, and that IL-21 functions as an autocrine growth factor for IL-21-producing CD4(+) T cells.
18508588In this review, we discuss recent progress from studies on the biology of IL-21 and the role of this cytokine in the pathogenesis of autoimmunity.
18508588Recent studies have demonstrated that IL-21 plays an important and non-redundant role in a number of autoimmune animal models indicating that IL-21 could be a common modulator of the adaptive immune response towards self-tissue constituents in diseases such as systemic lupus erythematosus, models of rheumatoid arthritis, multiple sclerosis and type-1 diabetes.
18508588Also, the studies on the production of IL-21 in human autoimmune diseases and its behaviour on human cells in vitro are revealing the potential of IL-21 to exacerbate cellular processes that determine the course of autoimmune diseases.
18512782IL-1beta and IL-6 independently induced IL-21 secretion, but the presence of IL-21 alone was not sufficient for IL-17 production.
18515660Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine.
18515660We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis.
18515660In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment.
18515660We found that the IL-21 receptor is expressed on vascular ECs.
18515660Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth.
18515660The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes.
18515660Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation.
18515660Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.
18554885Cytokines IL-21, IL-10, and IL-6, activating STAT3, are crucial in B cells along with toll-like receptor (TLR) signals, whereas IL-2 is crucial in T cells.
18556671IL-21 promotes survival and maintains a naive phenotype in human CD4+ T lymphocytes.
18556671IL-21 is a key T-cell growth factor (TCGF) involved in innate and adaptive immune response.
18556671However, the full spectrum of IL-21 activity on T cells remains unclear.
18556671Here, we demonstrate that IL-21 primarily maintains the expression of specific naive cell surface markers such as CD45RA, CD27, CD62L and CCR7 on human CD4(+) T lymphocytes and that the expression of CCR7 induces cell migration by means of CCL21 chemoattraction.
18556671Nevertheless, IL-21 maintained cell cycle activation and expression of proliferation markers, including proliferating cell nuclear antigen and Ki-67, and triggered T-cell proliferation via TCR and co-stimulation pathways.
18556671Unlike IL-2, IL-21 decreased the expression of the anti-apoptotic Bcl-2 protein, which correlated with the absence of activation of the phosphatidylinositol 3'-kinase/Akt signaling pathway.
18556671Thus, IL-21 is a TCGF whose function is the preservation of a pool of CD4(+) T lymphocytes in a naive phenotype, with a low proliferation rate but with the persistence of cell cycling proteins and cell surface expression of CCR7.
18556671These findings strongly suggest that IL-21 plays a part in innate and adaptive immune response owing to homeostasis of T cells and their homing to secondary lymphoid organs.
18579794STAT3 is required for IL-21-induced secretion of IgE from human naive B cells.
18579794IL-21 has also been recognized for its ability to suppress IL-4-induced IgE production by murine B cells.
18579794Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells.
18579794Furthermore, there was a striking synergy between IL-4 and IL-21 on inducing IgE secretion by CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by more than 10-fold.
18579794IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent.
18591227Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10(-/-) and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10(-/-) mice.
18599325Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-beta signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo.
18602282Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation.
18602282However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells.
18602282Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules.
18602282Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function.
18602282This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.
18613830The role of IL-21 in regulating B-cell function in health and disease.
18613830SUMMARY: Interleukin-21 (IL-21) belongs to a family of cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private (or shared) receptors as well as the common cytokine receptor gamma-chain as a component.
18613830The receptor for IL-21 is widely distributed on lymphohematopoietic cells, and IL-21 plays many biologic roles, including maintenance and function of CD8(+) memory T cells and natural killer cells, as well as promoting the generation of Th17 cells in the mouse.
18613830One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation or death during humoral immune responses.
18613830Furthermore, increased IL-21 production is characteristic of certain autoimmune diseases and is likely to contribute to autoantibody production as well as pathologic features of autoimmune disease.
18613830In contrast, IL-21 may function as a co-adjuvant to enhance antibody responses and thereby facilitate host defense to malignances and infectious diseases.
18613830The critical role of IL-21 in promoting humoral immune responses makes it an important focus of potential therapeutic interventions in conditions characterized by either overproduction of pathogenic autoantibodies or under production of protective antibodies.
18679768One new lineage, which has come to be called Th17 cells, selectively produces proinflammatory cytokines including interleukin-17 (IL-17, A and F), IL-21, and IL-22.
18679768In conjunction with transforming growth factor beta-1 (TGFbeta-1), IL-6, IL-21, and IL-23, which activate the transcription factor, signal transducer, and activator of transcription 3 (Stat3), the expression of another transcription factor, retinoic acid-related orphan receptor-gammat (RORgammat) leads to the differentiation of Th17 cells in mice.
18683239Transcriptional profile of primary astrocytes expressing ALS-linked mutant SOD1.
18683239Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons.
18684916The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-beta, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation.
18684916Herein we show that RA enhances TGF-beta signaling by increasing the expression and phosphorylation of Smad3, and this results in increased Foxp3 expression even in the presence of IL-6 or IL-21.
18684941IL-2, IL-15, and IL-21, all of which signals through receptors containing the common gamma chain, induced expression of IL-10 in the IL-2-dependent cell lines as well as primary leukemic CTCL cells.
18684941However, only IL-2 and IL-15, but not IL-21, induced expression of FOXP3.
18694350BACKGROUND: IL-21, a recently described common gamma-chain cytokine, can induce the maturation and enhanced cytotoxicity of natural killer (NK) and CD8(+) T cells and proliferation of CD40-stimulated B cells.
18694350Exogenous IL-21 has antitumor effects in murine models via immunological mechanisms.
18694350In addition, IL-21 can also directly induce apoptosis in chronic lymphocytic leukemia cells and other B cell lymphomas.
18694350OBJECTIVE/METHODS: We examine preclinical and clinical data regarding anticancer therapy with IL-21.
18694350IL-21 biology is also provided.
18694350CONCLUSION: Three Phase I and II clinical trials with recombinant IL-21 have been completed, providing data on the safety and efficacy in subjects with advanced melanoma, renal cell carcinoma and non-Hodgkin's B cell lymphoma.
18707899Involvement of ERK-1/2 in IL-21-induced cytokine production in leukemia cells and human monocytes.
18707899Interleukin-21 (IL-21), a type I cytokine produced by activated T cells, has diverse effects on the immune system, but its ability to induce production of other cytokines is not well delineated.
18707899Here, we have evaluated IL-21-induced cytokine production in human monocytes and U937 leukemia cells.
18707899We found that IL-21 induces upregulation of a variety of cytokines from multiple cytokine families.
18707899We also found that IL-21 triggers rapid activation of ERK1/2.
18707899Neutralizing antibody to the IL-21R prevented both IL-21-induced cytokine production and IL-21-induced activation of ERK1/2.
18707899Inhibition of ERK1/2 activity by the ERK-selective inhibitor U0126 reverses the ability of IL-21 to upregulate cytokine production, suggesting that IL-21-induced cytokine production is dependent on ERK1/2 activation.
18779421PARTICIPANTS: One hundred thirty-four patients with sporadic ALS, 31 patients with familial non-superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects.
18779421MAIN OUTCOME MEASURES: We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment.
18779421The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges.
18854238Differentiation of Th17 cells correlated with the presence of cytophaga-flavobacter-bacteroidetes (CFB) bacteria in the intestine and was independent of toll-like receptor, IL-21 or IL-23 signaling, but required appropriate TGF-beta activation.
18925392Immune activation in advanced cancer patients treated with recombinant IL-21: multianalyte profiling of serum proteins.
18925392IL-21 in patients.
18947877The combination of IL-21 and IFN-alpha boosts STAT3 activation, cytotoxicity and experimental tumor therapy.
18947877Here we hypothesized that a combination of IFN-alpha and IL-21, a novel cytokine of the IL-2 family with anti-cancer effects, will increase the anti-cancer efficacy at sub-optimal cytokine doses.
18947877We show that the combined stimulation of target-cells with IFN-alpha and IL-21 triggers an increased STAT3 activation whereas the activation of other STATs including STAT1/2 is unaffected.
18947877In parallel, the combined stimulation with IFN-alpha and IL-21 triggers a selective increase in MHC class I expression and NK- and CD8(+) T-cell-mediated cytotoxicity.
18947877In an experimental in vivo model of renal carcinoma, the combined treatment of IFN-alpha and IL-21 also produces a significant anti-cancer effect as judged by an inhibition of tumor growth and an increased survival.
18947877Taken together our data show that the combined use of IFN-alpha and IL-21 boosts STAT3 signaling, cytotoxicity, and anti-tumor efficacy, suggesting that a combinatorial therapeutic use of these cytokines may benefit cancer patients.
18957104BACKGROUND: Redistribution of nuclear TAR DNA binding protein 43 (TDP-43) to the cytoplasm and ubiquitinated inclusions of spinal motor neurons and glial cells is characteristic of amyotrophic lateral sclerosis (ALS) pathology.
18957104Recent evidence suggests that TDP-43 pathology is common to sporadic ALS and familial ALS without SOD1 mutation, but not SOD1-related fALS cases.
18957104Furthermore, it remains unclear whether TDP-43 abnormalities occur in non-ALS forms of motor neuron disease.
18957104In addition, abnormally phosphorylated or truncated TDP-43 species were not detected in fractionated ALS mouse spinal cord or brain.
18957104Despite partial colocalisation of TDP-43 with SMN, depletion of SMN- and coilin-positive Cajal bodies in motor neurons of affected SMA mice did not alter nuclear TDP-43 distribution, expression or biochemistry in spinal cords.
18957104CONCLUSION: These results emphasise that TDP-43 pathology characteristic of human sporadic ALS is not a core component of the neurodegenerative mechanisms caused by SOD1 mutation or SMN deficiency in mouse models of ALS and SMA, respectively.
18957685This lineage is characterized by production of interleukin (IL)-17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells.
18981091The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands.
18981091The common gamma-chain (gamma c) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro.
18981102IL-21 stimulates human myeloma cell growth through an autocrine IGF-1 loop.
18981102IL-21 is a member of the type I cytokine family related most closely to IL-2 and IL-15.
18981102IL-21 is a pleiotropic cytokine, produced by T, NKT, and dendritic cells, which modulates lymphoid and myeloid cell functions.
18981102Besides its activities on normal lymphoid cells, it has been shown that IL-21 is a growth factor for myeloma cells.
18981102In the present study, we demonstrate that IL-21 generated myeloma colonies from 9 of 24 human myeloma cell lines (HMCL) in a collagen-based assay.
18981102We found that IL-21 induced tyrosine phosphorylation of STAT-3, STAT-1, and Erk1/2.
18981102Interestingly, an Akt activation was observed lately after 30 min to 1 h of IL-21 stimulation, indicating that this Akt phosphorylation could be due to an IGF-1 autocrine loop.
18981102This hypothesis was sustained both by the fact that IL-21 treatment induced an IGF-1 mRNA synthesis and that an antagonistic anti-IGF-1 receptor mAb (AVE1642) strongly inhibits the IL-21-induced clonogenicity.
18981102Thus, we demonstrated by quantitative PCR that IL-21 induced clonogenicity through an autocrine IGF-1 secretion in HMCL and primary myeloma cells.
18981102These results support that therapy against IGF-1R, which are presently under investigation in multiple myeloma, could be beneficial, not only to suppress IGF-1-mediated myeloma cell growth, but also IL-21-mediated myeloma cell growth.
19013502TDP-43 is a nucleic acid binding protein that accumulates, along with ubiquitin, in the cytoplasm of amyotrophic lateral sclerosis (ALS) motor neurons.
19013502Recently, it was reported that Cu/Zn superoxide dismutase type 1 (SOD1) familial amyotrophic lateral sclerosis (fALS) model mice do not mimic the TDP-43 changes seen in sporadic ALS, although they share a large number of other properties with the human disorder.
19017979Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment.
19020307IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells.
19020307Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (T(FH)) differentiation.
19026702We here sought to clarify the function of IL-21 in human B-cell IgE synthesis.
19026702IL-21 dramatically enhanced IgE production by human mononuclear cells, or purified total, naive, or memory B cells in the presence of IL-4 plus anti-CD40 mAb cross-linked with CD32-transfectants, and the production was strengthened with further addition of IL-10.
19026702We also observed that IL-21 promoted B-cell differentiation into plasma cells with increase of B-lymphocyte-induced maturation protein-1 (Blimp-1), but not X-box binding protein 1 (XBP-1), which was further accentuated by co-stimulation with IL-4 plus CD40 signaling.
19026702Thus, IL-21 is a strong inducer of IgE production in human beings concomitantly with AID expression and the differentiation into plasma cells.
19026702Our data suggest that IL-21 plays an important role in occurrence and the treatment of allergic disorders.
19034262Local IL-21 promotes the therapeutic activity of effector T cells by decreasing regulatory T cells within the tumor microenvironment.
19034262Interleukin-21 (IL-21) is an IL-2-related cytokine that has shown limited evidence of antitumor activity in murine models and early phase clinical trials.
19034262Effect of local IL-21 on T-cell responses within the tumor microenvironment, however, has not been extensively evaluated.
19034262Thus, we developed a stably transfected IL-21-secreting B16 melanoma cell line to test the effects of local IL-21 on endogenous and adoptively transferred T-cell responses.
19034262Tumors expressing IL-21 exhibited delayed growth in vivo, which was associated with an increase in activated systemic effector and memory CD8(+) T-cell responses.
19034262Local IL-21 also enhanced the therapeutic effects of adoptively transferred gp100-specific T cells and was synergistic with IL-2.
19034262These data suggest that local IL-21 enhances endogenous and adoptively transferred T-cell immunity through increased effector CD8(+) T cells and decreased CD4(+) regulatory T cells in the tumor microenvironment.
19062315The T helper 17 (Th17) cell lineage is important in inflammatory and autoimmune responses, via its ability to produce interleukin-17 (IL-17) and IL-21.
19062315The pathology was associated with an enhanced responsiveness of T cells to low levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21.
19062315IBP sequestered IRF-4 and prevented it from targeting the transcriptional regulatory regions of the genes that encode IL-17 and IL-21.
19062315Thus, IBP appears to be important in preventing T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.
19079168IL-21 comes of age as a regulator of effector T cells in the gut.
19079168IL-21 is essential for the differentiation of Th17 cells.
19079168IL-21 is also involved in recruiting T cells to the inflamed gut and eliciting the secretion of matrix-degrading enzymes by gut fibroblasts.
19100696IRF-4-binding protein is a critical negative regulator of IRF-4 function, regulating production of the cytokines IL-21 and IL-17.
19104447To clarify how TDP may be involved in ALS pathogenesis, clinical and pathological features in cases of sporadic ALS ([SALS] n = 18) and ALS1 (n = 6) were analyzed.
19104447In mutant SOD1 transgenic (G93A) mice at the end stage (median, 256 days), TDP-positive inclusions and TDP colocalization with SOD1 were also observed; nuclear TDP-43 immunoreactivity was highly correlated with life span in these mice.
19132915Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors.
19132915Th17 cells also secrete IL-21 to communicate with the cells of the immune system.
19132915The differentiation factors (TGF-beta plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORgammat, and RORalpha) involved in the development of Th17 cells have just been identified.
19139170The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.
19139170We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4(+) T cells upon T cell receptor stimulation.
19139170IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro.
19139170Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21.
19139170Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production.
19144318Furthermore, TGFbeta1 and IL-21 downregulated CXCR5 while upregulating CCR10 on plasmablasts, enabling their exit from GCs and migration toward local mucosa.
19159826Expression of interleukin-21, interleukin-21 receptor alpha and related type I cytokines by intravascular graft leukocytes during acute renal allograft rejection.
19159826Interleukin-21 (IL-21), a member of the type I cytokine family, regulates central functions of immunity.
19159826We analyze the mRNA expression of IL-21, IL-21 receptor-alpha (IL-21Ralpha) and family members IL-15, IL-2Rgamma, IL-21Ralpha, IL-15Ralpha, IL-2/15Rbeta, as well as IL-2Ralpha (CD25) in leukocytes isolated by vascular perfusion of rat renal allografts.
19159826Furthermore, IL-21 and IL-2Ralpha mRNA expression was strongly increased.
19159826The function of the IL-21/IL-21R system in monocytes and during acute allograft rejection remains to be established.
19161418Recent studies show that these cells can also express IL-17F, IL-22, and IL-21.
19164519IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice.
19164519IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice.
19164519IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells.
19164519IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.
19191304Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans.
19196197Role of IL-15 and IL-21 in viral immunity: applications for vaccines and therapies.
19196197Two recently discovered cytokines (IL-15 and IL-21) appear to be key regulators in this process.
19196197IL-21 induces natural killer cell maturation and IFN-gamma production and acts to enhance the proliferation of memory CD8(+) T cells, its effects being more pronounced when combined with IL-15.
19208913The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes.
19208913RESEARCH DESIGN AND METHODS: We generated IL-21R-deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic beta-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes.
19208913Conversely, overexpression of IL-21 in pancreatic beta-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-gamma, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas.
19208913CONCLUSIONS: This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes.
19230867Distinct response in maintenance of human naive and memory B cells via IL-21 receptor and TCL1/Akt pathways.
19230867Among them, IL-21 receptor (IL-21R) and T-cell leukemia 1 (TCL1) proto-oncogene were highly expressed in naïve B cells.
19230867IL-21 induced the proliferation of both naïve and memory B cells.
19233474IL-21 and IL-15 cytokine DNA augments HSV specific effector and memory CD8+ T cell response.
19233474Since, interleukin 15 (IL-15) and interleukin 21 (IL-21) are cytokines implicated in homeostatic control of CD8(+) T cell pool, we constructed and used expression plasmids coding for IL-15 (pIL-15) and IL-21 (pIL-21) to expand HSV specific CD8(+) T cells in an animal model.
19233474Our results showed that the IL-21 increased the frequency of CD8(+) T cells in the absence of antigen, although the magnitude of this response was dependent on TCR signaling.
19251638Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice.
19251638Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types.
19251638We now report the surprising finding that diminished synthesis (by 70%) within Schwann cells of a fully dismutase active ALS-linked mutant (SOD1(G37R)) significantly accelerates disease progression, accompanied by reduction of insulin-like growth factor 1 (IGF-1) in nerves.
19251638Thus, therapeutic down-regulation of dismutase active mutant SOD1 in familial forms of ALS should be targeted away from Schwann cells.
19251786Finally, removal of CD25(+) Tregs from the tumour site and lymphoid organs did not alter tumour growth with or without interleukin (IL)-2 or IL-21 immunotherapy.
19261537Interleukin-21 (IL-21)-mediated pathways in T cell-mediated disease.
19261537Interleukin-21 (IL-21) is produced mostly by activated CD4+ T cells and controls the differentiation and functional activity of effector T helper cells, counteracts the suppressive effects of regulatory T cells, and stimulates non-immune cells to make inflammatory mediators.
19261537IL-21-driven tissue damage has been demonstrated in a number of organs, such as the gut, pancreas, and brain.
19261537Therefore new treatment modalities to neutralise IL-21 in vivo would be a valuable addition to the therapeutic armamentarium to combat immune-mediated inflammation.
19261537Here we describe the emerging role of IL-21 in the initiation and progress of the tissue-damaging inflammatory response in immune-mediated pathologies.
19261692Transforming growth factor beta (TGF) together with IL-6 or IL-21 initiates the differentiation while IL-23 stabilizes the generation of T(h)17 cells.
19276257PURPOSE: Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8(+) T cells, natural killer (NK) cells, and other cell types.
19276257We report final clinical and biological results of a phase II study of recombinant human IL-21 (rIL-21) in patients with metastatic melanoma.
19283717Th17 cells were identified as an independent lineage of CD4(+) T cells that secrete a distinctive set of immunoregulatory cytokines, including IL-17A, IL-17F, IL-22, and IL-21.
19284521The secretion of IL-21 was stimulated as strongly with the peptide as with interferon-gamma.
19285080Interleukin-22 (IL-22) plays an important role in the regulation of immune and inflammatory responses in mammals.
19285080The IL-22 binding protein (IL-22BP), a soluble receptor that specifically binds IL-22, prevents the IL-22/interleukin-22 receptor 1 (IL-22R1)/interleukin-10 receptor 2 (IL-10R2) complex assembly and blocks IL-22 biological activity.
19285080Comparison of IL-22/IL-22BP and IL-22/IL-22R1 crystal structures shows that both receptors display an overlapping IL-22 binding surface, which is consistent with the inhibitory role played by IL-22 binding protein.
19289234TNF-alpha, IL-6 and IL-21 were also detectable in the SF of the majority of patients, and IL-15 levels were associated with IL-6 levels.
19322031Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice.
19322031To evaluate the therapeutic potential of human neural progenitor cells (hNPs) in amyotrophic lateral sclerosis (ALS), we transplanted hNPs or growth factor (GF)-expressing hNPs into the central nervous system (CNS) of mutant Cu/Zn superoxide dismutase (SOD1(G93A)) transgenic mice.
19322031Donor-derived cells engrafted and migrated into the spinal cord or brain of ALS mice and differentiated into neurons, oligodendrocytes, or glutamate transporter-1 (GLT1)-expressing astrocytes while some cells retained immature markers.
19322031These results imply that although implanted hNPs differentiate into GLT1-expressing astrocytes and secrete GFs, which maintain dying motor neurons, inadequate trophic support could be harmful and there is sexual dimorphism in response to GDNF delivery in ALS mice.
19322899BACKGROUND: Interleukin-21 (IL-21) is involved in T and NK cell activation and effector response and promotes Th17 cell differentiation.
19322899Here we investigated IL-21 receptor (IL-21R) expression in inflamed mucosa of inflammatory bowel disease (IBD) and evaluated its role in the induction of NK cell cytotoxicity and activation as well as Th17 differentiation.
19322899PB-NK cells from IBD patients produced higher levels of interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) than controls when stimulated with immobilized human IgG and IL-21.
19322899IL-21-primed IBD NK cells showed a more potent antitumor cytotoxicity to NK-sensitive K562 cells than controls.
19322899TNF, IFN-gamma) than controls when stimulated with IL-21 and anti-CD3.
19322899Importantly, IL-21 facilitated IBD CD4(+) T cell to differentiate into Th17 cells, characterized by increased expression of IL-17A and ROR gamma t.
19379791TDP-43 normally shows nuclear localization, but in CNS tissue from patients who died with ALS this protein mislocalizes to the cytoplasm.
19379791Disease specific TDP-43 species have also been reported to include hyperphosphorylated TDP-43, as well as a C-terminal fragment.
19379791Whether these abnormal TDP-43 features are present in patients with SOD1-related familial ALS (fALS), or in mutant SOD1 over-expressing transgenic mouse models of ALS remains controversial.
19379791Here we investigate TDP-43 pathology in transgenic mice expressing the G93A mutant form of SOD1.
19379791In contrast to previous reports we observe redistribution of TDP-43 to the cytoplasm of motor neurons in mutant SOD1 transgenic mice, but this is seen only in mice having advanced disease.
19379791However, we do not observe C-terminal TDP-43 fragments nor TDP-43 hyperphosphorylated species in these end stage mSOD mice.
19379791These studies suggest motor neuron degeneration in the mutant SOD1 transgenic mice is associated with TDP-43 histopathology.
19380638Consistent with their localization, IL-4 producers express high levels of CXCR5, ICOS, PD-1, IL-21, and BCL-6, a phenotype characteristic of T follicular helper (Tfh) cells.
19386463The only specific marker of sporadic amyotrophic lateral sclerosis (ALS), that represent about 90% of all cases, is neuropathological and based on the demonstration of motoneuronal degeneration associated with typical inclusions positive for ubiquitine and TDP-43.
19386463SOD1 gene can be considered as a genetic marker of ALS, and not a polymorphism, if the mutation has been shown to be pathogenic or to segregate to the disease in familial cases.
19386463Studies in series of ALS patients have shown that MR-spectroscopy and diffusion tensor imaging can detect cortico-spinal degeneration.
19386463In the future, a combination of biological, radiological and electrophysiological markers, rather than a single marker, may provide diagnostic tool for the diagnosis and follow-up of ALS patients.
19406833Recent studies indicate that the cytokines IL-21 and IL-22 are produced by Th17 cells and modulate immune responses.
19406833Our studies demonstrate that the LXR agonist T0901317 suppressed MOG(35-55)-induced expression of IL-21 and IL-22 mRNA in splenocytes derived from MOG(35-55)-immunized mice.
19423777IL-21 is required to control chronic viral infection.
19423777Using a mouse model of chronic viral infection, we demonstrated that interleukin-21 (IL-21) is an essential component of CD4+ T cell help.
19423777In the absence of IL-21 signaling, despite elevated CD4+ T cell responses, CD8+ T cell responses are severely impaired.
19423777CD8+ T cells directly require IL-21 to avoid deletion, maintain immunity, and resolve persistent infection.
19423777Thus, IL-21 specifically sustains CD8+ T cell effector activity and provides a mechanism of CD4+ T cell help during chronic viral infection.
19433802Transforming growth factor (TGF)-beta alone induces FoxP3(+) T(reg) cells, but together with IL-6 or IL-21 induces T(H)17 cells.
19443735In this study, we show that interleukin-21 (IL-21), likely produced by CD4+ T cells, directly influences the generation of polyfunctional CD8+ T cells and that the number of CD4+ T cells that produce IL-21 differs markedly between acute and chronic infections.
19443735IL-21 regulates the development of CD8+ T cell exhaustion and the ability to contain chronic lymphocytic choriomeningitis virus infection.
19443735Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control.
19478140Our studies using Il21r-deficient (Il21r-/-) mice now suggest that interleukin-21 (IL-21) is critical for the long-term maintenance and functionality of CD8+ T cells and the control of chronic lymphocytic choriomeningitis virus infection in mice.
19478140Cell-autonomous IL-21 receptor (IL-21R)-dependent signaling by CD8+ T cells was required for sustained cell proliferation and cytokine production during chronic infection.
19487306Our results show that CD8+IL-17+ cells from psoriasis-inflamed skin tissue produce TNF-alpha and IFN-gamma (Th1-related cytokines) as well as IL-17, IL-21, and IL-22 (Th17-related cytokines) efficiently.
19489126IL-21, has potent antitumor effects.
19489126As IELs resemble lymphocytes infiltrating neoplastic lesions, their response to IL-21 may be relevant in vivo.
19489126Here, IL-21 was shown to increase perforin-mediated cytotoxicity and serine esterase release by IELs.
19489126This IL-21-mediated up-regulation occurred without changes in IEL survival or cell division.
19489126Interestingly, the effects of IL-21 occurred without increased phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, STAT4, STAT5, extracellular signal-regulated kinase (ERK), or p38.
19489126IL-21 had no effect on Fas ligand (FL)- or tumour necrosis factor-alpha (TNF-alpha)-mediated cytotoxicity, but it down-regulated IL-15-stimulated expression of CD25 and CD94, indicating that it has both positive and negative actions.
19489126This functional profile is unique to human IELs, emphasizing that they are a distinct compartment of lymphocytes and that IL-21 may promote their role in tumour immunosurveillance.
19494286It has been demonstrated previously that IL-21, induced by IL-6, stimulates the expression of the nuclear receptors retinoic acid-related orphan receptor (ROR)gammat and RORalpha, which in turn induce expression of IL-17.
19494286We found that the impaired Th17 differentiation by E-FABP-deficient CD4(+) T cells was associated with lower levels of IL-21 expression in response to IL-6, as well as reduced expression of RORgammat and RORalpha.
19494286However, E-FABP-deficient CD4(+) T cells expressed significantly higher levels of the nuclear receptor peroxisome proliferator-activating receptor (PPAR)gamma than did wild-type CD4(+) T cells, and treatment with the PPARgamma antagonist GW9662 restored expression of IL-21, RORgammat, RORalpha, and IL-17 by E-FABP-deficient T cells to wild-type levels.
19494286Thus, taken together, our data indicate that expression of E-FABP by CD4(+) T cells contributes to the control of IL-6 stimulation of the IL-21/ROR/IL-17 pathway and to the Th17/Treg counterbalance.
19494838Interleukin-21 (IL-21) has been recently shown to modulate the growth of specific types of B-cell neoplasm.
19494838All MCL cell lines and tumors examined expressed the IL-21 receptor.
19494838Addition of recombinant IL-21 (rIL-21) in vitro effectively induced STAT1 activation and apoptosis in MCL cells.
19494838As STAT1 is known to have tumor-suppressor functions, we hypothesized that STAT1 is important in mediating IL-21-induced apoptosis in MCL cells.
19494838In support of this hypothesis, inhibition of STAT1 expression using siRNA significantly decreased the apoptotic responses induced by IL-21.
19494838To further investigate the mechanism of IL-21-mediated apoptosis, we employed oligonucleotide arrays to evaluate changes in the expression of apoptosis-related genes induced by rIL-21; rIL-21 significantly upregulated three proapoptotic proteins (BIK, NIP3 and HARAKIRI) and downregulated two antiapoptotic proteins (BCL-2 and BCL-XL/S) as well as tumor necrosis factor-alpha.
19494838To conclude, IL-21 can effectively induce apoptosis in MCL via a STAT1-dependent pathway.
19494838Further understanding of IL-21-mediated apoptosis in MCL may be useful in designing novel therapeutic approaches for this disease.
19496940TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations.
19496940The transactive response (TAR) DNA binding protein 43 (TDP-43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS-related disorders.
19496940In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62-immunoreactive (IR) neuronal inclusions co-localized with TDP-43.
19496940In three out of four SOD1-FALS and one of two non-SOD1-FALS cases, TDP-43-IR inclusions were absent despite the presence of p62 and/or ubiquitin-IR inclusions.
19496940However, a single TDP-43-IR neuronal inclusion co-localized with p62 and ubiquitin in one SOD1-FALS (His48Gln) case.
19531753Levels of IL-21 were similar in SF and plasma, whereas IL-23 was undetectable.
19535626TGF-beta, together with IL-6 and IL-21, promotes Th17 cell development.
19535626IL-6 and IL-21 induce activation of STAT3, which is crucial for Th17 cell differentiation, as well as the expression of suppressor of cytokine signaling (SOCS)3, a major negative feedback regulator of STAT3-activating cytokines that negatively regulates Th17 cells.
19535626In this report, we demonstrate that TGF-beta inhibits IL-6- and IL-21-induced SOCS3 expression, thus enhancing as well as prolonging STAT3 activation in naive CD4(+)CD25(-) T cells.
19549377This study was aimed to explore the effects of interleukin 21 (IL-21) on the anti-leukemia activity of cytotoxic T lymphocytes (CTL) induced by dendritic cells (DCs) in vitro.
19549377The effects of IL-21 on the mature DCs were also studied by the measurement of the phenotype of DC and the allogenic mixed lymphocytic reactions induced by DCs.
19549377Experiments were divided into 2 groups: test group in which IL-21 (200 ng/ml) was added in coculture of DC/CTL and control group in which no IL-21 (200 ng/ml) was added.
19549377The results showed that when cultured with IL-21, the quantity of CTL increased from (56.
19549377IL-21 had neither effect on the phenotype (CD1a, CD83, CD86, CD80 and HLA-DR) of mature DCs nor the allogeneic mixed lymphocytic reactions induced by DCs.
19549377Nevertheless, there is no effect of IL-21 on the function of mature DCs.
19549377These data indicate that IL-21 has a potential clinical value in the enhancement of anti-leukemia immunotherapy.
19561536Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes.
19561536As T cells themselves may serve as effective antigen-presenting cells (T antigen-presenting cells; TAPC) and may be useful in vivo as cellular vaccines, we examined whether CD8(+) T cells genetically modified to produce IL-21 could induce immune responses to tumor associated antigen peptides in healthy human leukocyte antigen-A2(+) donors.
19561536IL-21 modified TAPC similarly enhanced generation of functional CTL against melanoma antigen gp100 and the B-cell chronic lymphocytic leukemia associated RHAMM antigen.
19561536Antigen-specific CTL generated using IL-21 gene-modified TAPC had a central memory phenotype characterized by CD45RA(-), CD44(high), CD27(high), CD28(high), CD62L(high), and IL-7 receptor-alpha(high), contrasting with the terminal effector phenotype of CTL generated in the absence of IL-21.
19561536Thus, TAPC stimulation in the presences of IL-21 enhances proliferation of tumor antigen-specific T cells and favors induction of a central memory phenotype, which may improve proliferation, survival, and efficacy of T-cell based therapies for the treatment of cancer.
19563785IGF-1:tetanus toxin fragment C fusion protein improves delivery of IGF-1 to spinal cord but fails to prolong survival of ALS mice.
19570826Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells.
19570826IL-27-driven c-Maf expression transactivates IL-21 production, which acts as an autocrine growth factor for the expansion and/or maintenance of IL-27-induced Tr1 cells.
19570826Each of those elements is essential, because loss of c-Maf, IL-21-signaling, or ICOS decreases the frequency of IL-27-induced differentiation of IL-10-producing Tr1 cells.
19577286Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies.
19578362The Il17 promoter is BATF-responsive, and after T(H)17 differentiation, BATF binds conserved intergenic elements in the Il17a-Il17f locus and to the Il17, Il21 and Il22 (ref.
19587639Th17) cells are a distinct lineage of T cells that produce the effector molecules IL-17, IL-17F, IL-21, and IL-22.
19592276Here we show that activated human dendritic cells (DCs) induced naive CD4(+) T cells to become IL-21-producing Tfh-like cells through IL-12.
19592276CD4(+) T cells primed with IL-12 induced B cells to produce immunoglobulins in a fashion dependent on IL-21 and inducible costimulator (ICOS), thus sharing fundamental characteristics with Tfh cells.
19592276IL-12 also regulated IL-21 secretion by memory CD4(+) T cells.
19592276Thus, IL-12 produced by activated DCs regulates antibody responses via developing IL-21-producing Tfh-like cells and inducing IL-21 secretion from memory CD4(+) T cells.
19604260IL-6, IL-21), and recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity.
19604272To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects.
19604272The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction.
19616319For instance, IL-21 controls the differentiation and functional activity of T cells, B cells and NK cells, limits the differentiation of inducible regulatory T cells (Tregs), and makes T cells resistant to the Treg-mediated immunesuppression.
19616319Here, we focus on data supporting the pathogenic role of IL-21 in human inflammatory diseases and discuss pre-clinical studies that suggest that neutralization of IL-21 in vivo could be a new biological therapy to combat immune-mediated pathologies, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis and systemic lupus erythematosus.
19617297Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed.
19617351In the present study, we demonstrate that Tax1 transactivates the interleukin-21 (IL-21) and its receptor (IL-21R) genes in human T-cells.
19617351Isolated promoters of the IL-21 and IL-21R genes were activated by Tax1 in reporter assays, which further revealed that there were at least two Tax1-responsive elements in either the IL-21 promoter or the IL-21R promoter.
19617351Chromatin immunoprecipitation assay and gel mobility shift assay exhibited that the IL-21 promoter elements bound transcription factors AP-1 and NF-kappaB, and the IL-21R promoter elements were associated with AP-1 and interferon regulatory factor.
19617351Collectively, Tax1-dependent activation of these transcriptional factors presumably contributes to expression of the IL-21 gene and its receptor gene.
19617351Tax2 exhibited little, if any, or no induction of the IL-21 transcription in CD4+ T-cells, in contrast to Tax1.
19619516Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- mice: support for a role for TDP-43 in the physiological response to neuronal injury.
19619516We have performed axotomies in two different presymptomatic models of motor neuron degeneration, low molecular weight neurofilament knockout (NFL(-/-)) mice and mutant SOD1(G93A) transgenic (mtSOD1(G93A)) mice aged 6 weeks, and observed TDP-43 and PGRN expression patterns in axotomized spinal motor neurons over 28 days.
19619516These results further support that TDP-43 is involved in neurofilament mRNA metabolism and transport, and provide insight into the pathogenesis of motor neuron death in ALS in which NFL mRNA levels are selectively suppressed.
19632985New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain.
19632985Here, we show that the C terminus of the interleukin-22 receptor (IL-22R) recruits in a tyrosine-independent manner the coiled-coil domain of STAT3.
19632985Deletion of the C-terminal part of IL-22R dramatically decreased its ability to activate STAT3 and to mediate IL-22 activity in cell lines, demonstrating that preassociation of STAT3 with this cytokine receptor, independent from the interaction between the Src homology 2 domain and phosphotyrosines, is required for its full activity.
19644854OBJECTIVE: Interleukin-21 (IL-21) is a member of the type I cytokine superfamily that has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production.
19644854The expression of IL-21 receptor (IL-21R) is reduced in the B cells of patients with systemic lupus erythematosus (SLE), while serum IL-21 levels are increased both in lupus patients and in some murine lupus models.
19687290Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1.
19687290Using primary human CD8+ T cells, in this study, we identify IL-21 as a strong inducer of granulysin, demonstrate that IL-21 and IL-15 activate granulysin expression within CD8+ CD45RO+ T cells, and establish a role for Jak/STAT signaling in the regulation of granulysin within CD8+ T cells.
19687290We show that infection of PBMC from healthy donors in vitro with HIV-1 suppresses granulysin expression by CD8+ T cells, concomitant with reduced p-STAT3 and p-STAT5, following activation with IL-15 and IL-21.
19687290Of note, simultaneous signaling through IL-15 and IL-21 could partially overcome the immunosuppressive effects of HIV-1 on granulysin expression by CD8+ T cells.
19697878The mechanisms underlying selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain unknown.
19697878Dyslipidemia has been reported to have a protective effect in ALS patients.
19697878Although phase III trials revealed that creatine monohydrate and IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with lithium, NADPH oxidase inhibitor, free-radical scavenger, and ammonium tetrathiomolybdate.
19704117Th17) cells produce IL-17 but can also make tumor necrosis factor, interleukin (IL)-6, IL-10, IL-21, and IL-22.
19707593We report that robust changes in cytokine signal transduction occur during the progression of SLE in multiple immune cell subtypes including increased T cell responsiveness to IL-10 and ablation of Stat1 responses to IFNalpha, IFNgamma, IL-6, and IL-21, Stat3 responses to IL-6, Stat5 responses to IL-15, and Stat6 responses to IL-4.
19709902Interleukin-21 (IL-21) is a class I cytokine with antitumor properties due to enhanced proliferation and effector function of CD8(+) T cells and natural killer (NK) cells.
19709902Here we have explored the magnitude and time-course of cytostatics-induced lymphopenia in mice and investigated whether treatment with cytostatics influences the antitumor effect of IL-21 in mouse tumor models.
19709902Additive antitumor effects were observed after combining IL-21 with PLD, oxaliplatin and to less extent 5-FU but not irinotecan, and larger effect was observed when IL-21 administration was postponed relative to chemotherapy, suggesting that these agents may transiently impair immune function.
19709902Our results show that IL-21 therapy can be successfully combined with agents from different chemotherapeutic drug classes, i.
19709902II inhibitors (PLD), anti-metabolites (5-FU) and platinum analogs (oxaliplatin) provided that IL-21 therapy is delayed relative to chemotherapy.
19712464IL-21 is a crucial regulator of NK cell function, whose influence on IL-15-induced differentiation of CD34-lineage- cells has not been investigated previously.
19712464The present study was designed and conducted to address whether IL-21 might replace the stromal cell requirements and foster the IL-15-induced NK differentiation of human UCB CD34-lineage- cells.
19712464RESULTS: CD34-lineage- cells were maintained in liquid culture with Flt3-L and SCF, with the addition of IL-15 and IL-21, either alone or in combination.
19712464CD34-lineage- cells proliferated vigorously in response to IL-15 and IL-21 but not to IL-21 alone, and up-regulated phosphorylated Stat1 and Stat3 proteins.
19712464CD34-lineage- cells expanded by IL-21 in combination with IL-15 acquired lymphoid morphology and killer-cell immunoglobulin-like receptor (KIR)-CD56+CD16-/+ phenotype, consistent with pseudo-mature NK cells.
19712464IL-21/IL-15-differentiated cells expressed high levels of mRNA for Bcl-2, GATA-3 and Id2, a master switch required for NK-cell development, and harboured un-rearranged TCRgamma genes.
19712464From a functional standpoint, IL-21/IL-15-treated cells secreted copious amounts of IFN-gamma, GM-CSF and CCL3/MIP-1alpha, and expressed cell surface CD107a upon contact with NK-sensitive tumour targets, a measure of exocytosis of NK secretory granules.
19712464CONCLUSION: This study underpins a novel role for IL-21 in the differentiation of pseudo-mature lytic NK cells in a synergistic context with IL-15, and identifies a potential strategy to expand functional NK cells for immunotherapy.
19718623Th17 subset, determinant in fighting Gram-negative bacteria, fungi, and some protozoa, secretes IL-17, IL-21, and IL-22, with strong proinflammatory effects.
19721453Here we show that IL-6, IL-12, IL-21 and IL-23 are capable of inducing IL-21 expression in naïve CD4(+) T cells isolated from human tonsils, peripheral blood and cord blood.
19731362IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression.
19731362Interestingly, expression of the IL-22 receptor (IL-22R) also increased in epidermal lesions versus normal skin.
19731362IL-22R over-expression using an adenoviral vector to mimic psoriatic conditions in cultured keratinocytes significantly enhanced IL-17- and IL-22-induced production of IL-20 subfamily cytokines.
19731362Furthermore, IL-17 and IL-22 coordinately enhanced MIP-3alpha, IL-8, and heparin-binding EGF-like growth factor (HB-EGF) production, depending on the amount of IL-22R expression.
19731362Additionally, because IL-20 and IL-24 share the IL-22R with IL-22, the function of IL-20 and IL-24 was also increased.
19731362These data indicate that increased IL-22R expression in epidermal keratinocytes contributes to the pathogenesis of psoriasis through enhancing the coordinated effects of IL-22 and IL-17, inducing the production of the IL-20 subfamily, chemokines, and growth factors.
19738033Interleukin-21 (IL-21) is an important promoter for differentiation of human B cells into immunoglobulin (Ig)-secreting cells.
19738033Stimulation with IL-21 was far more effective than stimulation with IL-4 or IL-10.
19738033Moreover, spontaneous apoptosis of CD19(+) B cells from patients with CVID or IgAD was prevented by a combination of IL-21, IL-4, and anti-CD40 stimulation.
19738033Analysis of IL-21 and IL-21 receptor (IL-21R) mRNA expression upon anti-CD3 stimulation of T cells, however, showed no evidence for defective IL-21 expression in CVID patients and sequencing of the coding regions of the IL21 gene did not reveal any mutations, suggesting a regulatory defect.
19748983TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells.
19748983Th cell cytokines IL-17A and IL-21 have been assigned with pivotal roles in the regulation of such autoimmune diseases.
19748983By contrast, the expression of IL-21 does not seem to be limited to a single distinct Th cell subset.
19748983We discovered that poly(I:C) induced synthesis of both IL-17A and IL-21.
19748983Finally, we found that the IL-21-producing cells that were differentiated in response to poly(I:C) expressed the chemokine receptor CXCR3, which is important in the recruitment of T cells into inflamed joints in rheumatoid arthritis.
19748983This is the first report to show that the TLR3 ligand poly(I:C) can directly induce the synthesis of IL-17A and IL-21 and drive differentiation of human naive CD4+ T cells.
19760257Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis.
19760257The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43.
19760257We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.
19760257Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course.
19765545If we just limit our focus to inflammatory cytokines, the main topic of this commentary, the list seems never-ending: IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-27 and IL-33.
19822525The pro-inflammatory phenotype was characterized by high production of IFN-gamma, IL-6, IL-21 and IL-17 and low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and exhibited potent regulatory functions.
19822525Their FOXP3 expression was stable, independent of the activation state and it correlated with suppressive function and inversely with the production of IFN-gamma, IL-6, IL-21 and IL-17.
19833056Interleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, activated natural killer T cells, and T follicular cells, has been reported to play a crucial role in the tissue-damaging T cell response in various organs, such as gut, skin, pancreas, and joints.
19833056This pathogenic effect is strictly linked to the ability of IL-21 to enhance the functional activities of multiple immune and non-immune cells.
19833056Consistently, studies from various laboratories have shown that blockade of IL-21 limits the progression of T cell-mediated inflammatory diseases in mice.
19833056Here we review the present knowledge on the expression and role of IL-21 in T cell-mediated pathologies.
19840884In this review, the role of aberrant RNA metabolism in ALS is examined, including the evidence that a majority of the genetic mutations observed in familial ALS (including mutations in TDP-43, FUS/TLS, SOD1, angiogenin (ANG) and senataxin (SETX)) can impact directly on either gene transcription, pre-mRNA splicing, ribonucleoprotein complex formation, transport, RNA translation or degradation.
19840884The evidence that perturbed expression or function of RNA binding proteins is causally related to the selective suppression of the low molecular weight subunit protein (NFL) steady state mRNA levels in degenerating motor neurons in ALS is examined.
19840884These observations lead directly to the hypothesis that ALS can be viewed as a disorder of RNA metabolism, thus providing a novel pathway for the development of molecular pharmacotherapies.
19841542Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.
19841542Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival.
19841542In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1.
19841542Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor.
19841542Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease.
19912250Studies with cytokine-deficient mice or blocking of interleukin (IL)-17, IL-21 and IL-22 have resulted in a conflicting data set.
19913562Nitric oxide and peroxynitrite induce gene expression of interleukin receptors increasing IL-21, IL-7, IL-1 and oncostatin M in cardiomyocytes.
19913562There was a significant and 2-fold increase in IL-21 R and an increase of 1.
19915059Endogenous IL-21 restricts CD8+ T cell expansion and is not required for tumor immunity.
19915059IL-21 has antitumor activity through actions on NK cells and CD8(+) T cells, and is currently in clinical development for the treatment of cancer.
19915059However, no studies have addressed the role of endogenous IL-21 in tumor immunity.
19915059In this study, we have studied both primary and secondary immune responses in IL-21(-/-) and IL-21R(-/-) mice against several experimental tumors.
19915059We found intact immune surveillance toward methylcholanthrene-induced sarcomas in IL-21(-/-) and IL-21R(-/-) mice compared with wild-type mice and B16 melanomas showed equal growth kinetics and development of lung metastases.
19915059Galactosylceramide stimulation showed equal expansion and activation of NKT and NK cells and mounted a powerful antitumor response in the absence of IL-21 signaling, despite reduced expression of granzyme B in NKT, NK, and CD8(+) T cells.
19915059Surprisingly, host IL-21 significantly restricted the expansion of Ag-specific CD8(+) T cells and inhibited primary CD8(+) T cell immunity against OVA-expressing EG7 lymphomas, as well as the secondary expansion of memory CD8(+) T cells.
19915059However, host IL-21 did not alter the growth of less immunogenic MC38 colon carcinomas with dim OVA expression.
19915059Overall, our results show that endogenous IL-21/IL-21R is not required for NK, NKT, and CD8(+) T cell-mediated tumor immunity, but restricts Ag-specific CD8(+) T cell expansion and rejection of immunogenic tumors, indicating novel immunosuppressive actions of this cytokine.
19962321The cytokine interleukin-21 (IL-21) is known to enhance immune function, and in this study we have investigated its ability to boost the efficacy of chemoimmunotherapy-cyclophosphamide and adoptive cell transfer (ACT)-in the B16-OVA/OT-I murine model of malignant melanoma.
19962321IL-21 injection.
19965678Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas.
19965678Interleukin-21 (IL-21), a member of the IL-2 cytokine family, has diverse regulatory effects on natural killer (NK), T, and B cells.
19965678In contrast to other cytokines that are usually immunostimulatory, IL-21 can induce apoptosis of murine B cells at specific activation-differentiation stages.
19965678Herein we report that diffuse large B-cell lymphoma (DLBCL) cell lines exhibit widespread expression of the IL-21 receptor (IL-21R) and that IL-21 stimulation leads to cell-cycle arrest and caspase-dependent apoptosis.
19965678IL-21 also induces apoptosis in de novo DLBCL primary tumors but does not affect viability of human healthy B cells.
19965678Furthermore, IL-21 promotes tumor regression and prolongs survival of mice harboring xenograft DLBCL tumors.
19965678The antilymphoma effects of this cytokine are dependent on a mechanism involving IL-21-activated signal transducer and activator of transcription 3 (STAT3) up-regulating expression of c-Myc.
19997967BACKGROUND: Interleukin-21 (IL-21) is critical in the development of autoimmune diseases.
19997967The role of IL-21 in the pathogenesis of immune thrombocytopenia (ITP) remains unknown.
19997967MATERIALS AND METHODS: We examined the expression of IL-21, IL-17, and interferon (IFN)-gamma in ITP patients and controls by enzyme-linked immunosorbent assay and flow cytometry.
19997967RESULTS: IL-21 was expressed on both CD3(+)CD8(-) T cells and CD3(+)CD8(+) T cells by flow cytometry.
19997967Plasma IL-21 level and the percentage of CD3(+)CD8(-)IL-21(+) T cells and CD3(+)CD8(+)IL-21(+) T cells were significantly elevated in ITP patients compared to controls.
19997967Moreover, we found a significant positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th17 cells.
19997967In addition, a positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th1 cells was also found.
19997967CONCLUSION: Together, our results indicated a possible role of IL-21 in ITP patients correlated to Th17 and Th1 cells, and blockade of IL-21 may be a reasonable therapeutic strategy for ITP especially those with active disease.
20008292Our results demonstrate that NK cells require DNAM-1 for natural or cytokine (IL-2, IL-12, or IL-21) suppression of tumor metastases or their variants expressing CD70 or CD80.
20014999This pathogenic effect is strictly linked to the ability of IL-21 to control the functional activities of multiple immune and non-immune cells.
20014999For instance, IL-21 regulates the differentiation and function of effector CD4+ T helper cells; controls activation, proliferation, and survival of B cells and enhances the cytotoxic activity of CD8+ T cells and NK cells.
20014999IL-21 also inhibits the differentiation of inducible regulatory T cells (Tregs) and makes effector CD4+ T cells resistant to the Tregs-mediated immunesuppression.
20014999Additionally, IL-21 stimulates epithelial cells and fibroblasts to make chemokines and extracellular matrix proteases, respectively.
20014999Consistently, studies from various laboratories have documented the beneficial effect of IL-21 neutralization on the progression of inflammatory diseases in mice.
20014999Here we review the present knowledge on the expression and role of IL-21 in immune-mediated pathologies.
20048285IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans.
20048285We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro.
20048285In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro.
20048285STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
20054607IL-17, IL-21, IL-10, and IL-22 cytokines, and thus have broad effects on a variety of tissues.
20057909Our study is designed to investigate the alteration and possible function of IL-21 in the development of an experimental autoimmune uveitis (EAU) model.
20057909IL-17 levels in the supernatant of the cell culture upon IL-21 stimulation were assayed by enzyme-linked immunosorbent assay.
20057909Expression of IL-21 mRNA was significantly increased in cells of DLN and spleen in EAU compared with recovery phase mice and normal controls.
20057909Cells in EAU cultured with IL-21 combined with transforming growth factor-beta induced increased production of IL-17.
20057909CONCLUSION: The findings revealed that increased IL-21 and IL-21R expression may be involved in the development of EAU, possibly by promoting IL-17 secretion.
20059963Interleukin-21 (IL-21) is a pleiotropic cytokine that regulates T-cell, B-cell, NK-cell, and myeloid-cell functions.
20059963IL-21 binds with its cognate receptor complex, which consists of the IL-21 receptor (IL-21R) and the common gamma chain (gammac) receptor subunit.
20059963Overexpression study of WSB-2 showed the reduction of IL-21R expression and IL-21-induced signal transduction.
20059963On the other hand, small interfering RNA for WSB-2 enhanced the expression level of IL-21R and IL-21-induced STAT3 activation, indicating that WSB-2 negatively controls the receptor expression.
20059963This report provides the first evidence that WSB-2 is a regulator of IL-21R expression and IL-21-induced signal transduction.
20060740Plasma IL-7, IL-2, IL-4, IL-6, IL-10, IL-21, TNF-alpha, IFN-gamma and BAFF were measured by enzyme-linked immuno-sorbent assay or bead array.
20074273Interleukin 21 (IL-21) is produced by activated CD4(+) T cells.
20074273IL-21 enhances the proliferation, antigen-induced activation, clonal expansion, IFN-gamma production, and cytotoxicity of NK cells and T cells.
20074273The antitumor actions of IL-21 have been variously attributed to NK cell and CD8(+) T cell cytotoxicity, CD4(+) T cell help, NKT cells, and the antiangiogenic properties induced by IFN-gamma secretion.
20074273In clinical trials IL-21 has been well tolerated and induces a unique pattern of immune activation.
20074273IL-21 is therefore an excellent candidate for use in immune therapy.
20080768IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter.
20080768IL-21 is a potent B cell activator and plasma cell differentiation-inducer cytokine produced by CD4(+) T cells.
20080768In type I Burkitt lymphoma (BL) cell lines and in the conditional lymphoblastoid cell line (LCL) ER/EB2-5, IL-21 potently activated STAT3 and induced the expression of LMP-1, but not EBNA-2.
20080768The IL-21-treated type I Jijoye M13 BL line ceased to proliferate, and this was paralleled by the induction of IRF4 and the down-regulation of BCL6 expression.
20080768In the type III LCLs and BL lines, IL-21 repressed the C-promoter-derived and LMP-2A mRNAs, whereas it up-regulated the expression of LMP-1 mRNAs.
20080768The IL-21-treated type III cells underwent plasma cell differentiation with the induction of Blimp-1, and high levels of Ig and Oct-2.
20080768IL-21 might be involved in the EBNA-2-independent expression of LMP-1 in EBV-carrying type II cells.
20080768In light of the fact that IL-21 is already in clinical trials for the treatment of multiple malignancies, the in vivo modulation of EBV gene expression by IL-21 might have therapeutic benefits for the EBV-carrying malignancies.
20081380Differential effects of IL-2 and IL-21 on expansion of the CD4+ CD25+ Foxp3+ T regulatory cells with redundant roles in natural killer cell mediated antibody dependent cellular cytotoxicity in chronic lymphocytic leukemia.
20081380Since members of this family of cytokines are known to exhibit their effects on diverse immune cells, we have examined the effects of IL-21 on CLL patient derived regulatory T cell (Treg) induction, expansion and the inhibitory effect on natural killer cells in vitro.
20081380We demonstrate here the expression of IL-21 receptor in CD4(+)CD25(High) regulatory cells from CLL patients.
20081380In contrast to IL-2, the IL-21 cytokine failed to mediate expansion of regulatory T cells or induced expression of Foxp3 in CD4(+)CD25(Intermediate) or CD4(+)CD25(Dim/-) T cells in whole blood derived from CLL patients.
20081380Interestingly, in contrast to their differential effects on expansion of the CD4(+)CD25(+)Foxp3(+)T cells, IL-2 and IL-21 exhibited a redundant role in Treg mediated suppression of NK cell mediated antibody dependent cytotoxicity function.
20081380Given the infusion related toxicities and pro-survival effect of IL-2 in CLL, these studies provide a rationale to explore IL-21 as an alternate gamma chain cytokine in CLL therapy.
20090929Attempts to optimize IL-9 production by pbCD3/sCD28 and IL-4+TGF-beta stimulated resting memory CD4(+) T cells demonstrated that the addition of IL-1beta, IL-12, and IL-21 further enhance IL-9 production.
20099135Although a number of cytokines including IFN-alpha, IFN-gamma, IL-2, IL-12, IL-15, IL-18, IL-21, GM-CSF, and Flt-3 ligand have been shown to potentiate the immune response to vaccination in various experimental models, the full potential of cytokines as vaccine adjuvants remains to be established.
20101507Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells.
20101507IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity.
20101507Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21.
20101507We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1.
20101507Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNgamma and IL-2, but not IL-10.
20101507To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.
20107805TCR) signalling strength, CD28-mediated costimulation, B cell-derived inducible costimulator ligand signals, induction of c-maf and actions of cytokines, including interleukin (IL)-6 and IL-21, lead to upregulation of the transcriptional repressor B cell lymphoma 6 (Bcl-6) that drives T follicular helper (Tfh) cell differentiation.
20112107Th17) cells are a distinct lineage of T cells that produce the effector molecules IL-17, IL-17F, IL-21, and IL-22.
20112373RESULTS: Neutralization of TNFalpha exacerbated skin inflammation and markedly enhanced the expression of the proinflammatory cytokines IL-1beta, IL-6, IL-17, IL-21, and IL-22 but suppressed FoxP3 expression in the skin and reduced the number of FoxP3-positive Treg cells in the draining LNs.
20127485However, further studies are needed to unravel the interplay between IL-17A and other Th17 cytokines such as IL-17F, IL-22, and IL-21 in the pathoimmunological process of this crippling disease, in particular, whether regulating Th17 cell activity or specific combinations of Th17 cytokines will have additional value compared to neutralizing IL-17A activity alone.
20131264Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22, but not interleukin-21, in autoimmune experimental arthritis.
20131264In contrast, transforming growth factor beta1 (TGFbeta1)/IL-6 was a potent inducer of RORgammat, RORalpha, IL-17A, IL-17F, IL-21, and FoxP3 in these cells.
20131264CONCLUSION: IL-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of IL-22, but not IL-21, levels in autoimmune arthritis.
20139271Stimulation with PMA/ionomycin caused splenic CD4(+)PD-1(+) T cells to secrete high levels of IFN-gamma, IL-10, low levels of TNF-alpha, faint levels of IL-2, IL-21, and no IL-4, IL-17.
20153437IL)-10, IL-22, IL-26, lysozyme, toll-like receptor (TLR)1, TLR3, TLR4a, MyD88, and nuclear factor (NF)-kappaB activating protein-like were upregulated, but IL-1beta and tumor necrosis factor-alpha were downregulated at 12h post-infection; IL-21, complement component c3b, and NF-kappaB activating protein-like were downregulated, but MyD88 was upregulated at 24h post-infection.
20153795Enhancing therapy of B16F10 melanoma efficacy through tumor vaccine expressing GPI-anchored IL-21 and secreting GM-CSF in mouse model.
20153795In the present study, we developed the tumor vaccine expressing IL-21 in the GPI-anchored form together with secreting GM-CSFs and investigated its antitumor efficacy in C57BL/6 mouse model.
20153795The fusion genes containing IL-21 and the GPI anchor signal sequence were acquired by overlaping PCR, inserted into the downstream of two multi-clone sites in recombinant plasmid pRSC/GM-CSFs to form pRSC/IL-21-gpi-GM-CSFs that was transfected into the B16F10 cells.
20153795The tumor cell vaccine B16F10/IL-21-gpi-GM-CSFs was identified by reverse transcription PCR, IFA and FCM, respectively.
20153795The results showed that the pRSC/IL-21-gpi-GM-CSFs had no cell cycle and proliferative state impact on the B16F10 cells after transfected, and that the tumor vaccine B16F10/IL-21-gpi-GM-CSFs increased the cytotoxicities of NK cells and CD8(+)CTL, enhanced the level of serum IFN-gamma, augmented therapy of tumor effect and prolonged survival time in the tumor-bearing mice immunized with the tumor vaccine B16F10/IL-21-gpi-GM-CSFs.
20154440The clinical features of a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (ALS) are reported.
20154440Genetic studies failed to detect any mutations of the Cu/Zn superoxide dismutase-1 (SOD1) and Dynactin1 (DCTN1) genes, but revealed a single base pair change from wild-type adenine to guanine at position 1009 in TAR-DNA-binding protein (TDP-43), resulting in a methionine-to-valine substitution at position 337.
20154440The immunohistochemical study on autopsied brain of the proband's aunt showed TDP-43-positive cytoplasmic inclusions in the anterior horn cells of the spinal cord and in the hypoglossal nucleus, as well as glial cytoplasmic inclusions in the precentral gyrus, suggesting that a neuroglial proteinopathy was related to TDP-43.
20154440In conclusion, a characteristic clinical phenotype of familial ALS with initial bulbar symptoms occurred in this family with TDP-43 M337V substitution, the pathomechanism of which should be elucidated.
20167599The activities of IL-21 are mediated through binding to its cognate receptor complex composed of the IL-21 receptor private chain (IL-21Ralpha) and the common gamma-chain (gammaC), the latter being shared by IL-2, IL-4, IL-7, IL-9, and IL-15.
20167599The binding energy of the IL-21 ternary complex is predominantly provided by the high affinity interaction between IL-21 and IL-21Ralpha, whereas the interaction between IL-21 and gammaC, albeit essential for signaling, is rather weak.
20167599The design of IL-21 analogues, which have lost most or all affinity toward the signaling gammaC chain, while simultaneously maintaining a tight interaction with the private chain, would in theory represent candidates for IL-21 antagonists.
20167599We predicted the IL-21 residues, which compose the gammaC binding epitope using homology modeling and alignment with the related cytokines, IL-2 and IL-4.
20186935However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known.
20186935We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut.
20186935To assess the involvement of IL-12 and IL-23 in the production of IL-21, T-LPL were activated in the presence or absence of IL-12 or IL-23.
20186935RESULTS: The proportion of IL-21-producing CD4+ T-LPL was increased in IBD compared to controls.
20186935Activation of CD4+ T-LPL with IL-12 but not IL-23 enhanced the fraction of cells coexpressing IL-21 and IFN-gamma.
20186935TFH cells in LPL were identified by CXCR5 expression and expressed IL-21 both in IBD and controls; however, the fraction of IL-21-positive TFH cells was higher in Crohn's disease than in ulcerative colitis and controls.
20186935Treatment of CD4+ T-LPL with IL-12 enhanced the frequency of CXCR5+ IL-21-producing TFH cells.
20186935CONCLUSIONS: These findings indicate that in IBD IL-21 is mostly produced by CD4+ T-LPL coexpressing IFN-gamma, reinforcing the concept that distinct subsets of T cells can produce IL-21.
20190192IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice.
20190192In a xenogeneic adoptive transfer model, we have compared the therapeutic potency of CD19-specific human primary T cells that constitutively express interleukin-2 (IL-2), IL-7, IL-15, or IL-21.
20190192IL-7- and IL-21-transduced T cells were most efficacious in vivo, although their effector functions were not as enhanced as IL-2- and IL-15-transduced T cells.
20190192Both IL-15 and IL-21 overexpression supported long-term T-cell persistence in treated mice, however, the memory T cells found 100 days after adoptive transfer were phenotypically dissimilar, resembling central memory and effector memory T cells, respectively.
20192994IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis?Accumulating evidence from murine and human studies supports a key role for interleukin-17 (IL-17) and IL-21 in the pathogenesis of inflammatory arthritis.
20192994The pathways and molecular mechanisms that underlie the production of IL-17 and IL-21 are being rapidly elucidated.
20192994This review focuses on interferon regulatory factor 4 (IRF4), a member of the IRF family of transcription factors, which has emerged as a crucial controller of both IL-17 and IL-21 production.
20193734Heterogeneous expression and function of IL-21R and susceptibility to IL-21-mediated apoptosis in follicular lymphoma cells.
20193734IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies.
20193734We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells.
20193734RESULTS: IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples.
20193734The latter were also resistant to IL-21-mediated apoptosis.
20193734Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation.
20193734Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21-responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression.
20193734CONCLUSION: These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21-mediated effects in some FL cells.
20232451We sequenced the genes encoding superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TARDBP) and FUS in 99 sporadic and 17 familial ALS patients ascertained at Mayo Clinic.
20232451ALS patients and established the de novo occurrence of one FUS mutation.
20232451SOD1 mutations, while FUS and TARDBP mutations were excluded.
20232451IVS13-2A>G) affects the splice-acceptor site of FUS intron 13 and was shown to induce skipping of FUS exon 14 leading to the C-terminal truncation of FUS (p.
20357253Although all types of Th polarization profiles can lead to terminal chronic rejection, a correlation between shorter graft survival and the presence of Th17 cells that produce IL-17 and IL-21 was observed.
20357253The correlation between the expressions of activation-induced cytidine deaminase (the key enzyme of the germinal center reaction) and IL-21 suggests that Th17 could exert their deleterious effect by promoting lymphoid neogenesis, namely, the organization of inflammatory effectors into ectopic germinal centers in which a local humoral immune response is elicited.
20359360RNA and OAZ silencing resulted in reduced total IgG, ANA, interferon (IFN)-gamma, interleukin (IL)-10, IL-12 and IL-21, but elevated CCL2 levels in culture supernatants (P < 0.
20359360IL-21 levels (r = 0.
20363292Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins.
20363292Here, the mouse motor neuron-like NSC-34 cell line transiently transfected with human SOD1(G93A) fused to enhanced green fluorescent protein exhibited aggregates contrary to cells overexpressing wild-type human SOD1.
20363292The aggregates were immunoreactive for ubiquitin but not for the TAR DNA binding protein (TDP-43) that was found in the nucleus.
20363292These cells may be used to study mechanisms of pathogenesis associated with ALS and to test potential therapeutic compounds.
20364087This neutrophil recruitment was dependent upon epidermal Vgamma5+ gammadelta T cell production of IL-17, but not IL-21 and IL-22.
20370663Amyotrophic lateral sclerosis (ALS) is a debilitating and ultimately fatal indication that is the most prevalent adult-onset motoneuron disorder.
20370663ALS imparts tremendous suffering upon patients and caregivers alike.
20370663An important new discovery is the involvement of the TAR DNA binding protein (TDP-43) based upon genetic evidence and the presence of the cytosolic ubiquitylated TDP-43 aggregates found during post-mortem analysis of damaged motoneurons in the spinal cord of ALS patients.
20370663Superoxide dismutase SOD1 continues to be of interest for the approximately 20% of the familial ALS patients who have the inherited form of the disease ( approximately 15% of the total), but SOD1 does not appear to be as relevant as was once imagined for the sporadic patent population.
20375986IL-17 (IL-17A), IL-17F, IL-21, IL-22, and possibly also IL-9 produced by Th17 cells promote inflammation by directly causing tissue injury and enhancing secretion of pro-inflammatory cytokines and chemokines by resident cells.
20384523AREAS COVERED IN THIS REVIEW: This is a comprehensive review of IL-21 including its pharmacology and current developmental status.
20384523PubMed listed publications involving IL-21, including original research articles, reviews and abstracts.
20384523WHAT THE READER WILL GAIN: Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing.
20386464Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads to an increase in the number of Treg cells whereas IL-21 does not stimulate the induction of Treg cells.
20386464Also, adjuvant IL-21 administration may lead to immune enhancement without simultaneous induction of Treg cells.
20389285GMCSF and IL-21 initiates hypersignaling through the IL-21Ralpha chain with immune activating and tumoricidal effects in vivo.
20389285B16 melanoma cells gene-enhanced to produce GIFT-21 were immune rejected by syngeneic C57Bl/6 mice comparable to the effect of IL-21 alone.
20394077Recently, we reported that IL-21 induces granzyme B (GzmB) and GzmB-dependent apoptosis in malignant CD5(+) B cells from patients with chronic lymphocytic leukemia.
20394077IL-21 directly induced GzmB expression and secretion by CD5(+) B cells from several AD and from cord blood in vitro, and the simultaneous presence of BCR stimulation strongly enhanced this process.
20394077Furthermore, IL-21 suppressed both viability and expansion of CD5(+) B cells from SLE individuals.
20394077Moreover, our data suggest that IL-21 may have disease-modifying characteristics by inducing GzmB in CD5(+) B cells and by suppressing their expansion.
20406185Neuronal death in amyotrophic lateral sclerosis (ALS): what can we learn from genetics?Amyotrophic lateral sclerosis (ALS) is a difficult disease to study as it is mostly sporadic and rapidly progressive.
20406185Identification of genes causing familial ALS (FALS) has been instrumental in advancing our understanding of ALS pathogenesis, most notably with the use of mutant superoxide dismutase 1 (SOD1) models of disease.
20406185For 15 years SOD1 models have been the backbone of ALS research, but no effective reatments have been developed.
20406185However, recent advances have been made in the genetics of ALS with the identification of mutations in TAR DNA binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), both of which have roles in RNA-processing and gene expression.
20406185Molecular links between ALS and frontotemporal dementia (FTD) are also suggested by linkage of ALS-FTD to chromosome 9.
20406185The study of the genetics of sporadic ALS (SALS) has been less fruitful, although this may change as we enter the era of resequencing.
20406185Further important clues as to the causes of ALS will come from the identification of other gene mutations that cause FALS, variants that increase susceptibility to SALS, and genetic factors that modify the ALS phenotype.
20423656AIM: To detect the serum anti-nuclear antibody (ANA) and interleukin-21 (IL-21) levels in patients infected with hepatitis C virus (HCV), and study their impact on the liver function of HCV patients.
20423656METHODS: Enzyme-linked immunosorbent(ELISA) assays were used to detect the serum ANA and IL-21 levels in 96 cases of HCV-IgG positive sera, as well as 30 cases of HCV-IgG negative sera.
20423656RESULTS: HCV patients have abnormal liver function significantly and their average IL-21 level was much lower than the control group.
20423656The IL-21 level of HCV patients with ALT < or = 40 U/L or ALT > 40 U/L were markedly reduced.
20423656CONCLUSION: The production of ANA and IL-21 do help to control the progress of hepatitis and reduce the damage to liver cells in HCV patients.
20424514Using phage display, we generated a panel of optimized neutralizing antibodies against the human and mouse receptors for interleukin 21 (IL-21), a cytokine that is implicated in the pathogenesis of many types of autoimmune disease.
20435882The amplification of interleukin-17 (IL-17) production by G-CSF occurs in both CD4 and CD8 conventional T cells and is dependent on, and downstream of, G-CSF-induced IL-21 signaling.
20445344In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity.
20445344We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival.
20445344Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells.
20445344Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy of IT administration of IL-21 was due to a local rather than systemic effect.
20445344IT administration of IL-21 led to enlarged tumor-draining lymph nodes (LNs), with increased naive lymphocyte numbers and proliferation of activated lymphocytes, suggesting that local administration of IL-21 generally benefits the tumor microenvironment and activates tumor-draining LNs.
20445344Overall, our data suggest that IL-21 augments CD8 T-cell-mediated antitumor immunity through increased proliferation and effector function and acts both on tumor-infiltrating CD8 T cells as well as on the draining LNs.
20445344IT administration led to superior CD8 T-cell proliferation, effector function, and antitumor efficacy, suggesting that IT administration of IL-21 may be clinically useful in patients with unresectable tumors.
20451460ICOS(hi) host CD4 T cells and IL-21 expression.
20451460Greater female IL-21 expression, a product of Tfh cells, was seen in CD8 intact --> F1 and although reduced was still greater than male CD8 depleted --> F1 mice.
20488794Furthermore, this diet resulted in low mRNA expression levels of IL-17, IFN regulatory factor 4, IL-21, IL-22, and IL-23 without alteration of other genes, such as RORgammat, TGF-beta, IL-6, IL-25, and IL-27 in the small intestine ileum.
20519643Follicular helper T (T(FH)) cells, defined by expression of the surface markers CXCR5 and programmed death receptor-1 (PD-1) and synthesis of IL-21, require upregulation of the transcriptional repressor Bcl6 for their development and function in B cell maturation in germinal centers.
20519643We have explored the role of B cells and the cytokines IL-6 and IL-21 in the in vivo regulation of Bcl6 expression and T(FH) cell development.
20519643Bcl6 nor PSGL1 downregulation, suggesting these events preceded T-B cell interactions, although they were required for full development of the T(FH) cell phenotype, including CXCR5 and PD-1 upregulation, and IL-21 synthesis.
20519643Bcl6 upregulation and T(FH) cell differentiation were independent of IL-6 and IL-21, revealing that either cytokine is not absolutely required for development of Bcl6(+) T(FH) cells in vivo.
20532127Interleukin-21 (IL-21) is an inflammatory cytokine and produced by activated T cells.
20532127The biologic functions of IL-21 have not yet extensively studied.
20532127And then, the change of IL-21 and VEGF production in HaCaT by UVB irradiation was examined.
20532127Not only IL-21 but also VEGF production was enhanced by UVB irradiation.
20532127Next, to determine relationship of enhanced production of IL-21 and VEGF, we detected VEGF production after neutralization of IL-21.
20532127VEGF production was reduced by IL-21 neutralization, which indicates that the IL-21 is involved in the VEGF production.
20532127In addition, it seems that IL-21 plays a role in the angiogenic process in skin via the modulation of VEGF production.
20536649IL-15 and IL-21 significantly decreased in AU and CU, but IgE increased.
20536649CU with a positive autologous serum skin test were more likely to be associated with longer course and higher CD3(+), B cells and IL-21, and lower IgE (P < 0.
20536649Moreover, a significant correlation was found between IL-21 and IgE (r = 0.
20536649Our findings supported the concept that both humoral immunity and cellular immunity dysregulation in the pathogenesis of urticaria - mainly related to the decrease of the serum levels of IL-15 and IL-21 - may induce the increasing expression of IgE produced by B cells.
20540648Further analysis of IL-27-driven Tr1 cells have identified a critical role of the transcription factor avian musculoaponeurotic fibrosarcoma v-maf and of IL-21 in the generation of IL-27-induced Tr1 cells.
20554001IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-6, TGF-beta) production in splenocytes was decreased dramatically on day 18 following CFA immunization.
20570967Several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are characterized by the presence of misfolded proteins, thought to trigger neurotoxicity.
20570967Some familial forms of ALS (fALS), clinically indistinguishable from sporadic ALS (sALS), are linked to superoxide dismutase 1 (SOD1) gene mutations.
20570967Using transgenic G93A-SOD1 mice, we found that spinal cord motor neurons, accumulating mutant SOD1 also over-express the small heat shock protein HspB8.
20570967Using motor neuronal fALS models, we demonstrated that HspB8 decreases aggregation and increases mutant SOD1 solubility and clearance, without affecting wild-type SOD1 turnover.
20571486HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22.
20571486We have analyzed the production of the effector cytokines interleukin (IL)-17, IL-21, and IL-22 in gluten-reactive CD4(+) T cells of celiac disease patients, either cultured from small intestinal biopsies or isolated from peripheral blood after an oral gluten challenge.
20571486Combining intracellular cytokine staining with DQ2-α-II gliadin peptide tetramer staining of intestinal polyclonal T-cell lines, we found that gluten-specific T cells produced interferon-γ (IFN-γ) and IL-21, but not IL-17 or IL-22, even if other T cells of the same lines produced these cytokines.
20571486We conclude that gluten-reactive T cells produce IL-21 and IFN-γ, but not IL-17.
20571486Their production of IL-21 suggests a role for this cytokine in the pathogenesis of celiac disease.
20623510Cytokines such as interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and type I interferons constitute pivotal factors involved in the maturation, activation, and survival of NK cells.
20625092BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies.
20625092Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear.
20625092OBJECTIVE: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment.
20625092Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis.
20644736Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients.
20644736Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients.
20644736Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1.
20644736These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme.
20644736Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients.
20644736Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation.
20644736The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.
20652041IL-21 has an important role in the control of the growth, survival, differentiation, and function of both T and B cells, and excessive production of IL-21 has been associated with the development of multiple immune-mediated diseases.
20660710IL-21 production from follicular Th cells and subsequent humoral immune responses.
20660710Moreover, the development of IL-21-producing CXCR5(+) Tfh-like cells was significantly increased in BTLA(-/-) CD4(+) T cells compared with WT CD4(+) T cells.
20660710These results suggest that BTLA signaling suppresses IL-21 production from Tfh cells and subsequent Tfh cell-mediated IgG responses.
20677335IL-21 is produced in excess in the inflamed intestine of patients with IBD mostly by activated CD4+ T helper cells co-expressing interferon-gamma and follicular T helper cells.
20677335Moreover, both in vitro and in vivo studies indicate that excessive IL-21 production leads to the activation of multiple signaling pathways that expand and sustain the ongoing mucosal inflammation.
20682664Increased interleukin 21 (IL-21) and IL-23 are associated with increased disease activity and with radiographic status in patients with early rheumatoid arthritis.
20682664RESULTS: Patients with early-stage RA had significantly increased plasma levels of IL-21 and IL-23, but not IL-17A, compared to patients with chronic RA and healthy volunteer controls.
20682664CONCLUSION: Our results show a significant association between plasma levels of IL-21 and IL-23 and disease activity in RA, supporting the hypothesis that IL-21 and IL-23 are important pathogenic factors of this disease.
20693196Study of this strain and related gene-manipulated strains has revealed roles for multiple cytokines, including interleukin (IL)-6, IL-18, and IL-21, in disease pathogenesis.
20697052OBJECTIVE: To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.
20697052DESIGN, SETTING, AND PARTICIPANTS: Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non-superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls.
20697052Main Outcome Measure We identified 3 index cases of familial ALS carrying the p.
20697052All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.
20697052CONCLUSIONS: Three apparently unrelated families with familial ALS carrying the p.
20697158Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice.
20697158Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders.
20697158IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders.
20697158Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21.
20697158We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells.
20697158Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice.
20697158Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.
20699640Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons.
20699640As with other age-dependent neurodegenerative disorders, ALS is linked to the presence of misfolded proteins that may perturb several intracellular mechanisms and trigger neurotoxicity.
20699640Proteins involved in the intracellular degradative systems, signaling pathways and the human TAR DNA-binding protein TDP-43 are major components of these inclusions.
20699640Using in vitro and in vivo models of mutant SOD1 associated familial ALS (fALS), we and other groups demonstrated that protein misfolding perturbs one of the major intracellular degradative pathways, the ubiquitin proteasome system, giving rise to a vicious cycle that leads to the further deposit of insoluble proteins and finally to the formation of inclusions.
20728492ALS pathogenesis: recent insights from genetics and mouse models.
20728492For the vast majority of cases of amyotrophic lateral sclerosis (ALS) the etiology remains unknown.
20728492After the discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial ALS, several transgenic mouse lines have been generated with various forms of SOD1 mutants overexpressed at different levels.
20728492For instance, the toxicity of mutant SOD1 seems unrelated to copper-mediated catalysis but rather to formation of misfolded SOD1 species and aggregates.
20728492Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport.
20728492Following the discovery of mutations in the TARDBP gene linked to ALS, there have been some reports of transgenic mice with high level overexpression of WT or mutant forms of TDP-43 under strong gene promoters.
20728492However, these TDP-43 transgenic mice do not exhibit all pathological features the human ALS disease.
20826721IL-21 induces death of marginal zone B cells during chronic inflammation.
20826721Interleukin-2 (IL-2) and IL-21 share activities in the control of T- and B-cell maturation, proliferation, function, and survival.
20826721However, opposing roles for IL-2 and IL-21 have been reported in the development of regulatory T cells.
20826721To dissect unique, redundant, and opposing activities of IL-2 and IL-21, we compared T- and B-cell development and function in mice lacking both IL-2 receptor α (IL-2Rα) and IL-21R (double knockouts [DKO]) with single knockout and wild-type (WT) mice.
20826721The absence of IL-2Rα resulted in overproduction of IL-21 by IFN-γ-producing CD4(+) T cells, which induced apoptosis of marginal zone (MZ) B cells.
20826721Our results highlight key roles of IL-2 in inhibiting IL-21 production by CD4(+) T cells and of IL-21 in negatively regulating MZ B-cell survival and antibody production.
20846186In amyotrophic lateral sclerosis (ALS), affecting the motoneurones of the central nervous system (CNS), stem cell-based therapy aims to replace dying host motoneurones by transplantation of cells in disease-affected regions.
20846186AIM: To determine the profile of seven trophic factors expressed by mesenchymal stem cells (MSC) and neural stem cells (NSC) upon stimulation with CNS protein extracts from SOD1-linked ALS rat model.
20846186CONCLUSIONS: These results suggest that inherent characteristics of different stem cell populations define their healing potential and raise the concept of ALS environment in stem cell transplantation.
20848219Interleukin-21 (IL-21) is a new member of the type I cytokine superfamily, which binds to a composite receptor that consists of a private receptor (IL-21R) and the common cytokine receptor γ chain.
20848219Recently, increasing evidence has shown that IL-21 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases because of its pro-inflammatory and immune-mediated properties.
20848219In addition, blockade of the IL-21/IL-21R pathway ameliorated disease in animal models of RA and significantly inhibited inflammatory cytokine production in vitro.
20933009The presence of GSPE decreased the levels of IL-21, IL-22, IL-26 and IL-17 production by human CD4(+) T cells in a STAT3-dependent manner.
20933032Mutations in the CuZn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43) genes are linked to familial amyotrophic lateral sclerosis, ALS1 and ALS10, respectively.
20933032In addition, TDP-43 is a major component protein of the ubiquitinated aggregates observed in sporadic ALS (SALS) patients.
20933032However, it remains unclear whether these ALS groups partly have a shared pathogenesis.
20933032In the present study, we demonstrate that mutant SOD1, but not wild-type SOD1, interacts with TDP-43 by co-immunoprecipitation assays using cultured cells and G93A mutant SOD1 transgenic mice.
20933032Deletion mutants of TDP-43 with or without nuclear localization sequence interacted with mutant SOD1.
20933032TDP-43 was detected both in the nuclear and cytosolic fractions, suggesting that mutant SOD1 interacts with TDP-43 in the cytoplasm.
20933032Mutant SOD1 overexpression led to an increased amount of mutant SOD1 and, to some extent, its interacting proteins including TDP-43 in the detergent-insoluble fraction.
20933032These results indicate that mutant SOD1 could affect the solubility/insolubility of its interacting proteins including TDP-43 through physical interactions.
20933032Our findings may contribute to the understanding of links among SALS, ALS1 and ALS10.
20934207METHODS: We assessed T(H)17 responses of PBMCs to Candida and non-Candida species stimuli by measuring IL-17, IL-22, IL-21, IL-6, IL-23, and IFN-γ cytokine production using cytokine arrays and intracellular cytokine-producing cell numbers and proliferation with flow cytometry.
20942785Amyotrophic lateral sclerosis (ALS) is an incurable disease resulting from the deterioration of motor neurons.
20942785The only drug that is available to treat ALS is riluzole, which extends survival by just 2-3 months.
20942785Thus, new therapeutic directions are being sought to prolong the lifespan of ALS patients.
20942785Since the discovery of SOD1 as a genetic determinant of ALS in 1993, SOD1-models of ALS have been extensively employed for the development of ALS therapeutics.
20942785In this review, we present several of the genetic contributors to both sporadic and familial forms of ALS and discuss their potential as therapeutic targets for this devastating disease.
20944558Stimulation of normal intestinal explants with tumor necrosis factor-α (TNF-α), but not interferon-γ (IFN-γ) or IL-21, reduced IL-25 synthesis.
20954185The induction of SLE in the mice was associated with an increase in B cell Toll-like receptor 7 expression, increased serum levels of BAFF, interleukin-6 (IL-6), and tumor necrosis factor α, and induction of T cells expressing IL-21.
20957227Sorted human CD19+CD27+ B cells were retrovirally transduced with the human B cell lymphoma (BCL)-6 and BCL-XL genes, and subsequently cultured in the presence of CD40-ligand and IL-21.
20959407Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg.
20959407IL-21 was tolerated and had dose-dependent pharmacodynamics.
20967127These TDP-43 abnormalities are seen when TDP-43 is mutated, such as in familial ALS, but also in FTLD, caused by null mutations in the progranulin gene.
20967127They are also found in many patients with sporadic ALS and FTLD, conditions in which only wild type TDP-43 is present.
20967127Mutant TDP-43 (A315T mutation) induced a motor axonopathy characterized by short axonal outgrowth and aberrant branching, similar, but more severe, than that induced by mutant SOD1.
20967127Interestingly, progranulin also rescued the mutant TDP-43 induced axonopathy, whilst it failed to affect the mutant SOD1-induced phenotype.
20977918The administration of IL-21 upregulated cytotoxic effector function and the expression of the costimulatory molecule CD28.
20977918Moreover, IL-21 promoted antiviral activity while not inducing HIV-1 replication in vitro.
20977918Thus, IL-21 may be a favorable molecule for immunotherapy and a suitable vaccine adjuvant in HIV-infected individuals.
20980695ICOS stimulation induced c-MAF, RORC2, and T-bet expression in these cells, leading to increased secretion of interleukin-21 (IL-21), IL-17, and interferon-γ (IFN-γ) compared with cells stimulated with CD28.
21037578Notably, antigen-primed plasma cells failed to induce interleukin 21 (IL-21) or the transcriptional repressor Bcl-6 in naive helper T cells and actively decreased these key molecules in antigen-activated T(FH) cells.
21043049The messenger RNA (mRNA) levels of IL-17, IL-21, and IL-23 were enhanced in the allografts compared with the control (P<0.
21043049Correlation analysis showed significant correlations between IL-17 and IL-6 and TGF-β and between IL-17 and IL-21 and IL-23.
21047796Th17 transcriptome revealed that the levels of mRNA that encode RORγt, IL-17A, IL-17F, IL-23R, and IL-22, were reduced by 1,25-D(3), whereas IL-21 and aryl hydrocarbon receptor mRNA remained unchanged.
21047960In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8(+) T cell function and control of persistent viral infections.
21047960To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment.
21047960HIV-specific triggering of IL-21 by CD4(+) T cells was significantly enriched in these persons (P = 0.
21047960IL-21-secreting CD4(+) T cells was characteristic for subjects with persistent viremia and progressive disease.
21047960IL-21 responses were mediated by recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21(+) CD4(+) T cells in acute infection resulted in lower viral set points (P = 0.
21047960Moreover, IL-21 production by CD4(+) T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8(+) T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8(+) T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding.
21047960These data suggest that HIV-1-specific IL-21(+) CD4(+) T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance for vaccine design.
21058223Therapeutic implications of the IL-21: IL-4 receptor system in children with common variable immunodeficiency syndrome.
21058223Ternary complexes of the IL-21 respectively IL-4 receptor were set-up by homology modeling and ligand-interaction was examined by molecular dynamics (MD) simulation.
21058223RESULTS: Stimulation with IL-21, IL-4 and CD40L uniformly induced IgG and IgA production in B cells from all tested patients by initiation of both CSR and AID-independent Ig production.
21058223No mutations were found in the coding regions of the IL21 or IL21R genes and no distinct HLA allele or extended haplotype could be correlated with the amount of Ig production or the gene expression pattern induced by IL-21.
21058223MD simulations of the modelled receptor complexes showed that IL-4 and IL-21 are both able to bind to IL-4R and IL-21R complexes in an interchangeable manner.
21060047Serum IL-21 level and IL-21 messenger RNA (mRNA) expression by peripheral blood mononuclear cells (PBMCs) were determined by enzyme-linked immunosorbent assay and by reverse transcriptase-polymerase chain reaction, respectively.
21060047Interleukin 17 and interferon γ levels in the supernatants of PBMCs and CD4(+) T cells cultured with anti-CD3 and anti-CD28 antibodies in the presence or absence of recombinant IL-21 were detected by enzyme-linked immunosorbent assay.
21060047RESULTS: The results showed a significantly increased serum IL-21 level, as well as higher IL-21 mRNA expression by PBMCs, in patients having chronic or recurrent active VKH disease compared with patients having inactive VKH disease and with controls.
21060047In vitro experiments showed that recombinant IL-21 significantly increased IL-17 production by PBMCs and by CD4(+) T cells from patients and from controls.
21060047However, recombinant IL-21 did not affect interferon γ expression by PBMCs or by CD4(+) T cells.
21060047CLINICAL RELEVANCE: Findings from the present study suggest that IL-21 may be a potential target in the development of therapy for VKH disease.
21076067GM-CSF and IL-21 induces tumor-antigen-specific immunity.
21076067We have previously shown that the fusion of GM-CSF and IL-21 (GIFT-21) possesses a potent immune stimulatory effect on myeloid cells.
21085192Stimulation of Sézary cells or healthy CD4+ T cells with the common-γ chain cytokine IL-21 results in a strong activation of STAT3, and subsequent upregulation of miR-21 expression.
21107711Interleukin-21(IL-21) is the most recently discovered member of the type-I cytokine family.
21107711Structurally, IL-21 shows homology to IL-2, 4, and 15 proteins.
21107711Many previous studies have identified that IL-21 was associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.
21107711Moreover, association of IL-21 and IL-21R polymorphisms with susceptibility to SLE have been reported.
21111405Aberrant production of IL-21 by T cells is critical for the development of type 1 diabetes (T1D) in NOD mice.
21111405The pathogenic effects of IL-21 are partly due to its ability to promote the generation of T(H)-17 cells.
21111405Interferon Regulatory Factor (IRF4) is a crucial regulator of IL-17 and IL-21 production.
21111405We recently found that the serine-threonine kinase ROCK2 phosphorylates IRF4 and regulates its ability to control IL-17 and IL-21 production.
21111405We furthermore demonstrate that ROCK inhibition corrects the abnormal IRF4 function in NOD T cells and diminishes their production of IL-17 and IL-21.
21116820Increased plasma levels of IL-21 and IL-23 in spondyloarthritis are not associated with clinical and MRI findings.
21116820Furthermore, to investigate the cellular origins of the cytokines, paired mononuclear cells from blood and synovial fluid were examined for the expression of IL-17A, IL-21, and IL-23R using multicolor flow cytometry.
21116820Both IL-21 and IL-23 levels were increased in plasma from SpA patients compared with healthy volunteers (P < 0.
21116820IL-21 and IL-23 (r = 0.
21116820No association between individual levels of IL-17A, IL-21, and IL-23 with C-reactive protein (CRP), MRI changes, and clinical scoring (BASMI, BASFI, and BASDAI) were observed.
21116820The frequency of CD4+CD45RO+ T cells expressing IL-21 and IL-23R was increased in the inflamed SpA joint compared to peripheral blood (P < 0.
21116822Expression of IL-17A and its positive regulators IL-21 and IL-23 was present in atherosclerotic lesions, significantly upregulated in atheromas of symptomatic patients (p = 0.
21116822IL-17A and IL-21 showed a strong correlation (p = 0.
21116822Furthermore, treatment with a HMG-CoA reductase inhibitor or acetylsalicylic acid showed reduced levels of IL-21, IL-23 and VCAM1 (all p < 0.
21119608Apart from IL-1β and TNF, several other cytokines including IL-6, IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor and IL-8 (a chemokine) have also been shown to be implicated in OA and could possibly be targeted therapeutically.
21155836Th17 cells produce IL-17A, IL-17F, IL-22, and IL-21, of which IL-17A and IL-17F mediate many of the downstream pathologic functions of these cells.
21159862Mouse models of chronic viral infection demonstrate that interleukin-21 (IL-21), produced primarily by CD4 T cells, is required for the generation and maintenance of functionally competent CD8 T cells and viral containment.
21159862We reasoned that preserved IL-21 production during HIV-1 infection would be associated with enhanced CD8 T cell function, allowing improved viral control.
21159862Here we analyzed the ability of CD4 and CD8 T cells to produce several cytokines in addition to IL-21 ex vivo following stimulation with overlapping HIV-1 peptides.
21159862Both CD4 and CD8 T cells were able to produce IL-21 in response to HIV-1 infection, with the latter cell type more closely associated with viral control.
21159862Furthermore, IL-21-producing HIV-1-specific CD4 T cells (compared to those producing other cytokines) were the best indicator of functional CD8 T cells.
21159862Our results demonstrate that HIV-1-specific IL-21-producing CD8 T cells are induced following primary infection and enriched in elite controllers, suggesting a critical role for these cells in the maintenance of viremia control.
21160047Functional characterization of a nonmammalian IL-21: rainbow trout Oncorhynchus mykiss IL-21 upregulates the expression of the Th cell signature cytokines IFN-gamma, IL-10, and IL-22.
21160047In mammals, IL-21 is a common γ chain cytokine produced by activated CD4(+) T cells and NKT cells that acts on multiple lineages of cells.
21160047Although IL-21 has also been discovered in birds, amphibians, and fish, to date, no functional studies have been reported for any nonmammalian IL-21 molecule.
21160047IL-21 maintained the expression of CD8α, CD8β, and IgM at a late stage of stimulation when their expression was significantly decreased in controls and increased the expression of the Th cell markers CD4, T-bet, and GATA3.
21160047This study helps to clarify the role of IL-21 in lower vertebrates for the first time, to our knowledge, and suggests IL-21 is a likely key regulator of T and B cell function in fish.
21174612CONCLUSIONS: the combination of sunitinib 50 mg at the '4 weeks on/2 weeks off' schedule and 10 microg/kg IL-21 was not tolerated due to hematological DLTs.
21175418IL-21 is an immune activator that also mediates suppression via IL-10.
21175418Interleukin-21 (IL-21) is a pleiotropic type I cytokine that is produced predominantly by CD4(+) T cells and natural killer T (NKT) cells.
21175418Although IL-21 production is relatively restricted to these two populations of immune cells, its targets are numerous, including multiple lympho-hematopoietic as well as non-hematopoietic lineages.
21175418The effects of IL-21 are specific not only to the target cell type, but also depend on the developmental stage of the target cell as well as the available co-stimulatory signals.
21175418Accordingly, IL-21 functions not only as a strong inducer of differentiation and proliferation but also as a pro-apoptotic factor.
21175418Although most of the effects of IL-21 are immunostimulatory, it has become clear that one of the cytokines that is potently induced by IL-21 in a number of lymphoid lineages is interleukin-10 (IL-10), one of the most immunosuppressive cytokines.
21175418The seemingly contradictory actions of IL-21 and IL-10 and the consequences of their co-expression are currently being explored in numerous infectious models, autoimmune diseases, and tumor responses.
21175418This review seeks to critically evaluate the evidence concerning the regulation of IL-10 by IL-21 in a number of lineage subsets as well as to discuss the potential positive versus deleterious roles that this co-expression may play in a range of disease models.
21204603Immunization with DNA vaccine expressing herpes simplex virus type 1 gD and IL-21 protects against mouse herpes keratitis.
21204603In this study, we developed a DNA vaccine expressing HSV-1 glycoprotein D (gD) and mouse interleukin-21(IL-21) and intramuscularly inoculated mice 3 times at 2-week intervals with a total of 300 ?g/mouse.
21204603The results showed that the DNA vaccine pRSC-gD-IL-21 generated higher levels of antibody, IFN-? and IL-4, and enhanced the splenocyte proliferative response to gD as well as the cytotoxic activity of splenocytes and NK cells to target cells compared with the response in either the pRSC-gD or mock plasmid pRSC immunized mice.
21204603Importantly, the pRSC-gD-IL-21 ameliorated herpes keratitis severity and time course after corneal infection with HSV-1.
21204603The findings suggest that the DNA vaccine pRSC-gD-IL-21 may induce an immune response that can limit HSV-1 infection and development of herpes keratitis in the immunized mice.
21206487Th17 CD cells also produce interferon-γ (IFNγ), IL-21, and IL-22.
21206487CONCLUSIONS: Gliadin-specific Th17 cells are present in the mucosa of CD patients having a dual role in the pathogenesis of the disease as they produce proinflammatory cytokines (such as IL-17, IFNγ, IL-21), mucosa-protective IL-22, and regulatory TGFβ, which actively modulates IL-17A production by T cells in the celiac mucosa.
21214545Interleukin-21 (IL-21) exerts critical functions in T helper type 17 (Th17) cell development.
21214545However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear.
21214545Here we showed that IL-21 induced the differentiation of human naive CD8(+) T cells into Tc22 cells without the expression of IL-17.
21214545The IL-21 induced naive CD8(+) T cells to produce IL-22 in greater amounts than memory CD8(+) T cells.
21214545In addition, we demonstrated that IL-21 promoted the proliferation and increased the expression of IL-21 receptors on activated naive CD8(+) T cells.
21214545Furthermore, IL-21 increased the expression of granzyme B molecules.
21214545Analysis of molecular mechanisms indicated that IL-21 induced phosphorylation of signal transducers and activators of transcription 1, 3 and 5 in CD8(+) T cells.
21214545Overall, our data indicated that IL-21, an effector cytokine produced by CD4(+) T cells, might mediate the cross-talk between CD4(+) and CD8(+) T cells through the production of IL-22.
21227406Although the suppressive effect of IL-21 via the induction of IL-10 in mouse model has been defined, the inhibitory effect of IL-21 in humans is not well understood.
21227406In the present study, we showed that IL-21 induced IL-10 production by human naive CD4(+) T cells.
21227406IL-21 increased the expression of IL-21R on activated naïve CD4(+) T cells.
21227406Further analysis indicated that IL-21 induced phosphorylation of STAT1, STAT3 and STAT5 in activated naïve CD4(+) T cells.
21227406In addition, IL-21 maintained the expression of CD16 on monocytes via the production of IL-10 by human naïve CD4(+) T cells.
21227406Taken together, our data indicated that IL-21 had a modulating effect on monocytes at least in part by inducing IL-10 production.
21237169In the induction phase of AIH, splenic CD4(+) T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6(+) inducible costimulator (ICOS)(+) interleukin (IL)-21(+) IL-21 receptor (IL-21R)(+) follicular helper T (T(FH)) cell phenotype.
21237169In addition, IL-21 produced by T(FH) cells drove CD8(+) T-cell activation.
21279808Th17 cells, characterized by production of IL-17, IL-22, and IL-21, have been implicated in the pathogenesis of autoimmune diseases, like rheumatoid arthritis and multiple sclerosis, but also play an important role in host defense and mucosal immunity.
21281812IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain.
21281812In this study we investigated IL-21 and IL-21 receptor (IL-21R) expression in MS lesions by in situ hybridization and immunohistochemistry.
21281812We detected strongly IL-21(+) infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4(+) cells.
21281812Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons.
21281812These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons.
21281961METHODS: T(H)17 cells were differentiated from naive human CD4(+) T cells in the presence of TGF-β and IL-21.
21281961RESULTS: IVIg inhibits the differentiation and amplification of human T(H)17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21, and CCL20.
21301041Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle weakness that reflects degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem, and spinal cord.
21301041Most ALS cases are sporadic, but about 5%-10% are familial.
21301041The majority of familial ALS (FALS) cases follow an autosomal dominant inheritance pattern, and include the following mutations: ALS1, Cu/Zn superoxide dismutase (SOD1); ALS3; ALS4, senataxin; ALS6, fused in sarcoma (FUS); ALS7; ALS8, vesicle-associated membrane protein; ALS9, angiogenin; ALS10, TAR DNA-binding protein (TARDBP); and ALS11/FIG4.
21301041Some of these gene mutations are rarely seen in sporadic ALS cases.
21338381Th17-produced cytokine profile including interleukin (IL)-17, IL-6, IL-21, IL-22, IL-23 and tumour necrosis factor (TNF)-α, which have proinflammatory functions, suggests it as an important factor in immunopathogenesis of MS, because the main feature of MS pathophysiology is the neuroinflammatory reaction.
21346313BACKGROUND: The causes of amyotrophic lateral sclerosis (ALS) are largely unknown.
21346313METHODS AND RESULTS: In the present study, we applied the brain-permeable iron chelators VK-28 and M30 in a G93A mutant superoxide dismutase 1 transgenic (SOD1(G93A)) mouse model of ALS and found that VK-28 and M30 significantly delayed disease onset, extended the life span and reduced spinal cord motor neuron loss.
21346313Moreover, we demonstrated that both iron chelators were able to decrease TDP-43 protein aggregation and the proapoptotic molecule Bax, and to enhance antiapoptotic protein Bcl-2 expression, in the ALS mice.
21362481In the present study, the ontogenetic expression of immune-related genes, including three complement components (C3-1, C3-2 and Bf/C2), two cytokines (IL-21 and type I IFN [IFN]), lysozyme (LZM), novel immune-type receptor (NITR-18), Ikaros (IK) and ceruloplasmin (CP) were characterized during different developmental periods (from 0 to 28 d post-hatch [dph]) in Japanese medaka.
21381156Importantly, recent findings suggest that beyond IL-17 production-Th17 cells may secret a plethora of other effector cytokines such as IL-21, IL-22, and IL-9- which is in part induced by its own IL-9 production.
21391901INTRODUCTION: IL-21, a new member of the type 1 cytokine superfamily, is produced by various subsets of CD4(+) T cells and binds to a composite receptor that consists of a specific receptor, termed IL-21 receptor and the common γ-chain subunit.
21391901Initially considered to be a critical regulator of T and B cell function, IL-21 is now known to regulate the activity of many other cell types, including both immune and non-immune cells.
21391901AREAS COVERED: In this review, we discuss the biological features of IL-21 and summarize recent advances in the pathogenic role of IL-21 in chronic inflammatory diseases.
21391901Moreover, we discuss why IL-21 blockers can have a place in the therapeutic armamentarium for patients with immune-mediated diseases and the potential risks of such treatments.
21391901EXPERT OPINION: Data emerging from studies in human and experimental models of autoimmunity suggest that IL-21 is critically involved in the initiation and/or progression of inflammatory reactions where self-reactive immune cells or antibodies cause damage in tissue.
21391901Thus, theoretically, targeting IL-21 could help attenuate the activation of inflammatory pathways and facilitate the resolution of tissue damaging immune responses.
21391901However, one should also take into consideration some potential risks that could derive from the blockade of IL-21.
21392369IL-21 (P = 0.
21423809IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation.
21423809Cytokines are important modulators of lymphocytes, and both interleukin-21 (IL-21) and IL-6 have proposed roles in T follicular helper (Tfh) differentiation, and directly act on B cells.
21423809Here we investigated the absence of IL-6 alone, IL-21 alone, or the combined lack of IL-6 and IL-21 on Tfh differentiation and the development of B cell immunity in vivo.
21423809The combined absence of IL-6 and IL-21 resulted in reduced Tfh differentiation and reduced Bcl6 protein expression.
21423809In contrast, we observed reduced germinal center formation only in the absence of IL-21.
21423809Absence of IL-6 had no impact on germinal centers, and combined absence of both IL-21 and IL-6 revealed no synergistic effect on germinal center B cell development.
21423809Studying CD4 T cells in vitro, we found that high IL-21 production was not associated with high Bcl6 or CXCR5 expression.
21423809Cumulatively, our data indicates that optimal Tfh formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh differentiation.
21463857WSB-1, a novel IL-21 receptor binding molecule, enhances the maturation of IL-21 receptor.
21463857Interleukin-21 (IL-21) is a pleiotropic cytokine that regulates T-cell, B-cell, NK-cell, and myeloid-cell functions.
21463857IL-21 binds with its cognate receptor complex, which consists of the IL-21 receptor (IL-21R) and the common gamma chain.
21502992Studies have shown that interleukin 22 (IL-22) is expressed at barrier surfaces and that its expression is dysregulated in certain human diseases, which suggests a critical role in the maintenance of normal barrier homeostasis.
21502992Consistent with that, studies of mouse model systems have identified a critical role for signaling by IL-22 through its receptor (IL-22R) in the promotion of antimicrobial immunity, inflammation and tissue repair at barrier surfaces.
21502992In this review we will discuss how the expression of IL-22 and IL-22R is regulated, the functions of the IL-22-IL-22R pathway in regulating immunity, inflammation and tissue homeostasis, and the therapeutic potential of targeting this pathway in human disease.
21511186This study describes a CD4+ T helper (Th) cell subset marked by coexpression of the cytokine interleukin 21 (IL-21) and the gut-homing chemokine receptor CCR9.
21511186CCR9+ Th cells expressed large amounts of IL-21, inducible T cell costimulator (ICOS), and the transcription factors Bcl6 and Maf, and also supported antibody production from B cells, thereby resembling T follicular B helper (Tfh) cells.
21511186However, in contrast to Tfh cells, CCR9+ Th cells displayed limited expression of CXCR5 and the targets of CCR9+ Th cells were CD8+ T cells whose responsiveness to IL-21 was necessary for the development of diabetes.
21511186Thus, CCR9+ Th cells are a subset of IL-21-producing T helper cells that influence regional specification of autoimmune diseases that affect accessory organs of the digestive system.
21518858Here, using AM14 site-directed transgenic rheumatoid factor (RF) mice, we report that B cells can be activated, differentiate, and isotype-switch independent of antigen-specific T-cell help, αβ T cells, CD40L signaling, and IL-21 signaling to B cells.
21518858However, T cells do dramatically enhance the response, and this occurs via CD40L and IL-21 signals.
21518963Serum levels of the proinflammatory cytokines IL-2, IL-6, interferon-γ, IL-17a, IL-21, and IL-23 were increased significantly, suggesting a T-helper 17 cell-mediated inflammatory state.
21519361IL10 receptor-A/-B expression, STAT3 activation in response to IL6, IL10, IL21, IL22 were analyzed by FACS and western blotting.
21524651Caspase-8 cleavage of the interleukin-21 (IL-21) receptor is a negative feedback regulator of IL-21 signaling.
21540448Profiling of secretory products by antibody arrays and subsequent ELISAs showed that the secretion of three proinflammatory factors (IL-17B, IL-21, TNFα) and three hematopoietic growth factors [GF; thrombopoietin and granulocyte (macrophage) colony-stimulating-factors] was reduced in adipocytes of ApN-Overex mice compared with wild-type mice.
21556354PVR after reattachment surgery than in patients with an uncomplicated postoperative course, whereas levels of IL-1β, IL-4, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12p70, IL-13, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-25, IL-33, TNF-α, IFN-γ, IGF-1, bFGF, HGF, and NGF were not (P>0.
21597988Twenty previously reported polymorphisms in genes encoding bovine interferon gamma (IFNG), IFNGR1, IFNGR2, IL22, IL22RA1, IL12RB1, IL12RB2, and IL23R were genotyped in a resource population of 446 dairy Holsteins with known MAP infection status, and logistic regression was used to assess the statistical association with a binomial MAP infection status phenotype.
21626001Familial and "sporadic" forms of ALS and lower motor neuron syndromes are known.
21626001In ALS, one consistent neuropathological feature is intraneuronal protein inclusions which arise from TDP-43, FUS, SOD1 or ataxin-2 aggregations.
21626001TDP-43, FUS, SOD1 and ataxin-2 are multifunctional DNA/RNA-binding proteins which are involved in transcription regulation.
21626001The elucidation of common pathways in the cascade of motor neuron degeneration is an essential point of departure for molecular genetically defined treatment strategies both in ALS and in hereditary and sporadic lower motor neuron syndromes.
21631495Here we focus on Th17 cells and their associated cytokines IL-17A, IL-17F, IL-21 and IL-22.
21647936Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of motor neurons.
21647936The causes of most cases of ALS are as yet undefined.
21647936We conclude that these neurotoxins act through different transcriptional inductions, and these changes may reflect an adaptative cellular response to the cellular stress induced by the neurotoxins involved in ALS in the presence of mutant human SOD1.
21651514Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder.
21651514The majority of cases are sporadic ALS (SALS), with 5-10% being familial ALS (FALS), and are inherited mostly as autosomal dominant.
21651514The screenings showed a single mutation in SOD1 (Asp109Tyr) and three in TARBDP (Ala382Thr, Gly295Ser, Gly294Val) in five unrelated ALS patients.
21651514This report enlarges the spectrum of clinical phenotypes associated with genetic mutations in SOD1 and TARDBP genes confirming the variability of phenotypes associated with the same mutation and emphasizes the importance of genetic analysis.
21664274The mammalian gamma-chain (γC) cytokine family consists of interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
21681565Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-α, which are produced by Th17 cells.
21681565Our study identified the significant elevation of serum IL-6, IL-21, IL-22, and resistin levels in psoriasis patients.
21687547IL-15, IL-21, and IL-23) could potently induce NK cell activation to secret high levels of proinflammatory cytokines (e.
21692955The frequencies of IL-21-secreting CD4+ T cells were higher in HB-ACLF (both P < 0.
21692955Serum IL-21 levels were highest (P < 0.
21692955Recovery from HB-ACLF was associated with reduced serum IL-21 levels (P = 0.
21692955CD4+ IL-21(+) T-cell frequency (P = 0.
21692955In summary, IL-21 has a causal role in the development of severe liver inflammation, which is upregulated in HB-ACLF and associated with severity of liver disease.
21706386SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments.
21706386Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure.
21706386This has led to the creation of animal models to further our understanding of the disease and identify a number of ALS-causing mechanisms, including mitochondrial dysfunction, protein misfolding and aggregation, oxidative damage, neuronal excitotoxicity, non-cell autonomous effects and neuroinflammation, axonal transport defects, neurotrophin depletion, effects from extracellular mutant SOD1, and aberrant RNA processing.
21706386Here we summarise the SOD1 and TDP-43 animal models created to date, report on recent findings supporting the potential mechanisms of ALS pathogenesis, and correlate this understanding with current developments in the clinic.
21727188In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21.
21727188Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22.
21750724The effect of adevofir dipivoxil treatment on the frequency of CD4(+)CXCR5(+) TFH cells, the concentrations of serum IL-2, IFN-γ, TNF-α, IL-4, IL-6, IL-10, IL-21, ALT, AST, HBsAg, HBsAb, HBeAg, HBeAb and HBV loads in IA patients were determined.
21760890One marker of the KIAA1109/IL-2/IL-21 candidate region differentiated potentials from celiac (rs4374642: χ2 = 7.
21760890The expression of IL-21 was completely suppressed in potentials compared to celiacs (p value = 0.
21768062METHODS AND RESULTS: IL-21 rs2055979, rs13143866, rs9992580, and rs4833837 were genotyped in 235 cases of RSM and 235 controls.
21768062Regression analysis was employed in assessing the contribution of IL-21 variants to the overall RSM risk.
21768062IL-21 haplotype [rs9992580/rs4833837/rs2055979/rs13143866] analysis revealed a lower frequency of the TGCG haplotype, and a higher frequency of the GGCG and GAAA haplotypes in patients, thus conferring protection from or a susceptibility to RSM by these haplotypes respectively.
21795048The proportion of Th17 cells and IL-17 secreting CD8(+)T cells were counted using flow cytometry, and serum levels of IL-6, IL-17, IL-21, IL-23, and transforming growth factor-beta (TGF-β) were measured by enzyme-linked immunosorbent assay.
21801431RESULTS: Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-α were observed in active RA patients than in 12 healthy controls (all P < 0.
21801431Levels of IL-6, IL-21, IL-23 and TNF-α were significantly decreased after anti-TNF-α therapy in responders.
21808264In the present study we show, that in the absence of CD40L, CD4(+) T cell-derived IL-21 induces differentiation of B cells into granzyme B (GzmB)-secreting cytotoxic cells.
21808264Using fluorescence-activated cell sorting (FACS) analysis, ELISpot and confocal microscopy, we demonstrate that CD4(+) T cells, activated via their T-cell receptor without co-stimulation, can produce IL-21, but do not express CD40L and rapidly induce GzmB in co-cultured B cells in an IL-21 receptor-dependent manner.
21808264Of note, we confirmed these results with recombinant reagents, highlighting that CD40L suppresses IL-21-induced GzmB induction in B cells in a dose-dependent manner.
21808264In contrast, no cytotoxic effects were found when effector B cells were activated with IL-2 instead of IL-21 or when target cells were cultured with IL-21 alone.
21808264CD40 ligand determines whether IL-21 induces differentiation of B cells into plasma cells or into granzyme B-secreting cytotoxic cells.
21815905Possible involvement of IL-21 and IL-10 on salivary IgA levels in chronic periodontitis subjects.
21815905The mRNA levels of IL-4, IL-10, IL-21, IL-21R, CD40L in the gingival biopsies were evaluated by quantitative real-time polymerase chain reaction.
21815905The mRNA levels for IL-21 was higher (P < 0.
21815905In conclusion, the upregulation of IL-21 and IL-10 and downregulation of IL-4 in periodontitis tissues may be collectively involved in the increased levels of salivary IgA in chronic periodontitis subjects.
21824785The role of IL-21 in hematological malignancies.
21824785IL-21, the newest member of the common γ-chain family of cytokines, has pleiotropic biological effects through regulating a variety of immune cells.
21824785Recently, the role of IL-21 in the treatment of cancers has been widely investigated.
21824785Expression of IL-21 and IL-21R has also been found in many types of hematological malignancies, such as chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and lymphoma.
21824785Through binding with IL-21R, IL-21 induces activation of different JAK/STAT signal transduction pathways and regulates proliferation or apoptosis of tumor cells.
21824785In this review, we will discuss the expression of IL-21/IL-21R and its effect in different types of hematological malignancies.
21829392FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis.
21829392Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients.
21829392Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein.
21829392Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS-related mutations, as well as their interactions with TARDBP and SOD1.
21829392In contrast, the two most frequent ALS-related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function.
21829392This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism.
21829392We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway.
21829392Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.
21829620Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation.
21829620Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice.
21829620These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well.
21834058Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the misfolding and aggregation of distinct proteins in affected tissues, however, the pathogenic cause of disease remains unknown.
21834058Recent evidence indicates that endoplasmic reticulum (ER) stress plays a central role in ALS pathogenesis.
21873521SOCS-1 expression and, thus, responsiveness to IL-7, can be regulated by IL-7 itself, as well as IFN-γ and IL-21.
21886804Subsequently, IL-21 acts in an autocrine fashion to expand and maintain the Tr1 cells induced in vivo by nasally administered anti-CD3.
21889323Along with IL-4, IL-7, IL-9, IL-15, and IL-21, IL-2 shares the common cytokine receptor γ chain, γ(c), which is mutated in humans with X-linked severe combined immunodeficiency.
21907555Interestingly, deletion of individual 'T(H)17 cytokines', such as IL-17A, IL-17F, IL-22 and IL-21, does not phenocopy the complete EAE-resistance of IL-23-deficient mice.
21924794IL-21 and signal transducer and activator of transcription 3 (STAT3) were also dysregulated in skin and whole blood, providing additional evidence for involvement of the IL-12 pathway and potential activation of the Th17 pathway.
21938013Autocrine IL-21 stimulation is involved in the maintenance of constitutive STAT3 activation in Sézary syndrome.
21938013In SS cells, STAT3 was strongly activated by IL-21, and increased expression of IL-21 and its receptor chains was observed in peripheral blood SS cells.
21938013IL-21 and IL-21R protein expression was detectable on neoplastic cells in SS skin biopsies.
21938013Using short-term culturing experiments, we demonstrate that IL-21 itself and the α-chain of the IL-2 receptor are STAT3 target genes in SS cells, thereby rendering cells more sensitive to stimulation with the T-cell proliferation and activating cytokine IL-2.
21938013Combined, our data point toward a pivotal role for an autocrine positive feedback loop involving IL-21 and consequent persistent STAT3 activation in the pathogenesis of SS, thereby indicating IL-21 and IL-21R as new therapeutical targets.
21943235IL-2, IL-7, IL-15 and IL-21, sharing a common receptor γ chain (c-γ), control T lymphocyte homeostasis and proliferation and play major roles in regulating cancer-immune system interactions.
21943235RESULTS: IL-2 and IL-21 gene expression was comparably detectable, with low frequency and at low extents, in PCA and BPH tissues.
21945025OBJECTIVES: IL-21 is a new pleiotropic cytokine involved in immune system regulation.
21945025DESIGN AND METHODS: We determined IL-21 in the plasma of hemodialyzed (HD) patients and healthy controls, and we tried to identify the factors which could affect its levels.
21945025RESULTS: Detectable levels of IL-21 were observed in the similar percent of HD patients and controls, but its concentration was twice lower in HD patients.
21945025The patients with detectable IL-21 had lower inflammatory state, reflected by IL-6 and TNF-α, compared to those with undetectable IL-21.
21945025The association was between IL-21 and the presence of glomerulonephritis (p<0.
21945025CONCLUSIONS: IL-21 is decreased in HD patients and is not affected by gender, age, inflammation, the vintage of HD, type of medication and type of used dialysis membrane.
21948944METHODS: Chronic colitis was induced in IL-21(-/-) and littermate control wild-type mice with three cycles of 1.
21948944RESULTS: Increasing expression of IL-21 was observed in chronic colitis, which showed functional importance, since IL-21 deficiency prevented chronic DSS-colitis development.
21948944Further, in the absence of IL-21, significantly fewer tumour nodules were detected, despite a similar extent of intestinal inflammation.
21948944IL-21-deficient mice.
21948944In tumour-bearing IL-21-deficient mice, intestinal inflammation was restored and partly dependent on interferon (IFN)-γ, whereas the inflammation in wild-type mice showed high IL-17A concentrations.
21948944In these rare tumours in IL-21-deficient mice, tumour cell proliferation (Ki-67) was decreased, while cell apoptosis was increased, compared with wild-type mice.
21948944Increased IFNγ expression in tumour-bearing IL-21-deficient mice led to increased tumour immunosurveillance mediated by cytotoxic CD8CD103 T cells targeting E-cadherin(+) colonic tumour cells and therefore limited tumour growth.
21948944CONCLUSION: These results indicate that IL-21 orchestrates colitis-associated tumorigenesis, leading to the hypothesis that high IFNγ and low IL-17A expression reduces tumour cell proliferation and increases tumour immunosurveillance.
21949017Additionally, we demonstrate in an infectious disease model that CD8-intrinsic CD40 signaling is important for optimal CD8 polyfunctionality, proliferation, T-bet upregulation, and IL-21 signaling, albeit in the context of CD8 rescue.
21955625On the other hand, children with active TB compared with HC showed markedly diminished production of type 1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), 2 (interleukin 4 [IL-4] and IL-13), and 17 (IL-17A, IL-21, and IL-23)-associated cytokines with no stimulation and in response to mycobacterial antigens.
21985374The hepatic expression of Th17 cell-related genes [retinoid-related orphan receptor gamma (ROR)γt, IL-17, IL-21 and IL-23] was also increased significantly in NASH patients compared to healthy controls.
21987656IL-21-deficient mice also developed fewer and smaller tumors compared with wild-type (WT) mice.
21987656Absence of IL-21 reduced signal transducer and activator of transcription 3 activation in tumor and stromal cells.
21987656Administration of a neutralizing IL-21 antibody to WT mice after the last DSS cycle decreased the colonic T cell infiltrate and the production of IL-6 and IL-17A and reduced the number of tumors.
21987656These observations indicate that IL-21 amplifies an inflammatory milieu that promotes CAC, and suggest that IL-21 blockade may be useful in reducing the risk of UC-associated colon cancer.
21996099After each dose of IL-21, increases were noted in frequency and mean fluorescence intensity of GrB and perforin expression in memory and effector subsets of CD8 T cells in peripheral blood (PB), in peripheral and mesenteric lymph node (LN) cells, in PB memory and effector CD4 T cells and in NK cells.
21996099In addition, PB CD27(+) memory B cells were 2-fold higher and serum SIV antibodies increased significantly after IL-21 administration.
21996099Thus, administration of IL-21 to chronically SIV infected viremic animals was safe, well tolerated and could augment the cytotoxic potential of T cells and NK cells, promote B cell differentiation with increases in SIV antibody titers without discernable increase in cellular activation.
21996099Further studies are warranted to elucidate the effects and potential benefit of IL-21 administration in the context of SIV/HIV infection and in SIV/HIV vaccine design.
22019586Idd3 mice played a central role in this differential Th17 cell development, and IL-21 signaling in APCs was pivotal to this process.
22019586These data suggest that the protective effect of the Idd3 locus is due, in part, to differential RA signaling in APCs and that IL-21 likely plays a role in this process.
22022259Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive.
22022259The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses.
22022259For this purpose, pharmacokinetic (PK) and pharmacodynamic (PD) data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers.
22022259We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected "training" data.
22022259The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent "validation" data in melanoma and renal cell carcinoma-challenged mice (R(2)>0.
22022259Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules.
22028219The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis.
22030011Impact of interleukin-21 in the pathogenesis of primary Sjögren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands.
22030011To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined.
22030011METHODS: Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured.
22030011Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass.
22030011LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry.
22030011Confocal microscopy was performed to further characterize the IL-21 positive cells.
22030011RESULTS: Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1.
22030011Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens.
22030011The more the lymphocyte infiltrated, IL-21 expression in LSGs showed a tendency to increase.
22030011Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5.
22030011CONCLUSIONS: Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels.
22030011The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs.
22030011These observations suggest that IL-21 may play an important role in primary SS pathogenesis.
22038405Copy number variations of interleukin-17F, interleukin-21, and interleukin-22 are associated with systemic lupus erythematosus.
22038405We examined CNVS of Th17 cell-related genes, including retinoic acid receptor-related orphan nuclear receptor γt, STAT-3, interleukin-6 (IL-6), transforming growth factor β, tumor necrosis factor α, IL-17A, IL-17F, IL-21, IL-22, IL-23A, CCL20, and CCR6, and levels of messenger RNA (mRNA) for IL-17F, IL-21, and IL-22.
22038405RESULTS: Genotype and allele frequencies for copy number amplifications of IL-17F, IL-21, and IL-22 were found to be significantly higher in SLE patients than in healthy controls.
22051914Amyotrophic lateral sclerosis (ALS) is a genetically diverse disease.
22051914At least 15 ALS-associated gene loci have so far been identified, and the causative gene is known in approximately 30% of familial ALS cases.
22051914TAR DNA-binding protein 43 is a major constituent of the ubiquitinated protein inclusions in ALS, providing a possible link between the genetic mutation and the cellular pathology.
22072931Protein misdirection inside and outside motor neurons in Amyotrophic Lateral Sclerosis (ALS): a possible clue for therapeutic strategies.
22072931Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness with no effective cure.
22072931Emerging evidence supports the notion that the abnormal conformations of ALS-linked proteins play a central role in triggering the motor neuron degeneration.
22072931In particular, mutant types of superoxide dismutase 1 (SOD1) and TAR DNA binding protein 43kDa (TDP-43) are key molecules involved in the pathogenesis of familial and sporadic ALS, respectively.
22072931Although SOD1 is a major cytosolic protein, mutated SOD1 has been localized to mitochondria, endoplasmic reticulum, and even the extracellular space.
22072931The nuclear exclusion of TDP-43 is a pathological hallmark for ALS, although the pathogenic priority remains elusive.
22072931The generation of mutant- or misfolded protein-specific antibodies would help to uncover the distribution and propagation of the ALS-linked proteins, and to design a therapeutic strategy to clear such species.
22072931Herein we review the literature regarding the mislocalization of ALS-linked proteins, especially mutant SOD1 and TDP-43 species, and discuss the rationale of molecular targeting strategies including immunotherapy.
22077059Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes.
22077059In rodent graft-versus-host disease (GVHD) models, anti-IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury.
22077059To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression.
22077059By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls.
22077059In a human xenogeneic GVHD model, human IL-21-secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels.
22077059Based on these findings, anti-IL-21 mAb could be considered for GVHD prevention in the clinic.
22080897IL-21 and IL-12 inhibit differentiation of Treg and TH17 cells and enhance cytotoxicity of peripheral blood mononuclear cells in patients with cervical cancer.
22080897OBJECTIVES: Interleukin 21 (IL-21) and IL-12 have been known to be effective antitumor agents.
22080897In this study, we evaluated whether IL-21 in combination with IL-12 could enhance the cytotoxicity of peripheral blood mononuclear cells (PBMCs) in patients with cervical intraepithelial neoplasia III and cervical cancer.
22080897Interleukin 2-stimulated PBMCs were cocultured with anti-human IL-21 neutralizing antibody, IL-21 alone, IL-12 alone, and IL-21 plus IL-12, respectively, as test groups.
22080897RESULTS: Compared with controls, IL-21 and IL-12 significantly elevated PBMC cytotoxicity against SiHa cells.
22080897Moreover, IL-21 plus IL-12 significantly elevated PBMC cytotoxicity in comparison to IL-21 alone and IL-12 alone.
22080897We also found that IL-21 plus IL-12 significantly decreased Treg and TH17 cell proportion in comparison to controls.
22080897Notably, IL-21 plus IL-12 significantly decreased TH17 cell proportion in comparison to IL-21 alone.
22080897Both IL-21 and IL-12 significantly decreased the apoptosis rate of PBMCs, whereas neither IL-21 nor IL-12 had significant effect on PBMC proliferation.
22080897CONCLUSIONS: The combination of IL-21 and IL-12 could efficiently stimulate PBMCs with cytotoxicity against SiHa cells, and the possible mechanisms may be due to down-regulated Treg and TH17 cell differentiation.
22098223RNA expression of interleukin (IL)-12, IL-15 and IL-21 in PP and the pulmonary mRNA expression of IFN-γ, TNF, IL-12a, IL-12rbl, IL-2rb and perforin 1 increased significantly (P < 0.
22099421Granulysin expression is significantly increased following exposure to IL-15 or Mycobacterium bovis BCG, but in contrast to our previous findings with CD8(+)T cells, expression is weakly activated by IL-21.
22108206The presence of germinal center centroblasts, follicular dendritic cells, activation-induced cytidine deaminase, and IL-21(+)PD1(+) follicular helper T cells in tLTs together with CD138(+) plasma cell accumulation around remodeled vessels in areas of immunoglobulin deposition argued for local immunoglobulin class switching and ongoing production.
22110656Moreover, our results indicate a specific cytokine expression profile along the EAE course characterized by no changes of IL10 and IL17 levels, decrease of IL21 on the peak, and high IL22 levels during the induction and peak phases that markedly decrease during recovery.
22113479IFN-γ, IL-21, and IL-10 co-expression in evolving autoimmune vitiligo lesions of Smyth line chickens.
22113479Elevated leukocyte infiltration in early and active SLV was accompanied by increased levels of cytokine expression, especially in IFN-γ, IL-10, and IL-21.
22118527This study shows that the IL-10-IL-21-STAT3 pathway is critical for memory CD8(+) T cell development after acute LCMV infection.
22118527In the absence of either interleukin-10 (IL-10) and IL-21 or STAT3, virus-specific CD8(+) T cells retain terminal effector (TE) differentiation states and fail to mature into protective memory T cells that contain self-renewing central memory T cells.
22118527Thus, memory CD8(+) T cell precursor maturation is an active process dependent on IL-10-IL-21-STAT3 signaling.
22131549Colonic mucosal mRNA expression of critical Th17 cell cytokines and chemokine receptors (IL-17F, IL-21, and CCR6) were lower, whereas expression of the Th17 cell suppressive cytokine, IL-27, was greater in Fat-1 mice compared to WT mice during chronic colitis (P < 0.
22133625Serum levels of interleukin 6 (IL-6), TNF-α, IL-32, IL-23, IL-17A, IL-21, and IL-22 were measured in patients with RA and 25 healthy controls.
22133625IL-21 in the sera compared to controls.
22133625IL-21 (p < 0.
22133625Serum IL-21 levels were positively correlated with levels of rheumatoid factor (r = 0.
22147555An expansion of IL-21-producing CD4+ T cells was also observed in patients with active GCA and correlated positively with Th17 and Th1 cell expansion.
22147555Immunohistochemical analysis revealed IFNγ, IL-17A, and IL-21 expression within inflammatory infiltrates.
22147555Stimulation of purified CD4+ T cells with IL-21 increased Th1 and Th17 cell frequencies and decreased FoxP3 expression.
22147555In contrast, blockade of IL-21 using IL-21R-Fc markedly decreased the production of IL-17A and IFNγ and increased FoxP3 expression.
22147555CONCLUSION: Our findings indicate that IL-21 plays a critical role in modulating Th1 and Th17 responses and Treg cells in GCA, and might represent a potential target for novel therapy.
22169719RESULTS: IL-21 levels increased gradually during the follow-up but did not reach the healthy levels.
22169719IL-21 correlated positively with the CD4 cells but not with CD8 T cells.
22178267Interestingly, splenocytes from mice treated with TCE for 24 weeks secreted significantly higher levels of IL-17 and IL-21 than did splenocytes from controls after stimulation with MDA-mouse serum albumin (MSA) or HNE-MSA adducts.
22181687BACKGROUND: Interleukin-21 (IL-21) controls the differentiation of T-helper Th17 cells and induces the production of IL-17 in this T-cell subtype.
22181687The aim of this study is to determine the relative expression of IL-21 in gingival tissues of chronic periodontitis patients and correlate/associate this expression with proinflammatory cytokines and clinical parameters of disease.
22181687The mRNA expressions of IL-21, IL-1β, IL-6, IL-17, IL-23, IL-10, and transforming growth factor-β1 (TGF-β1) were quantified using real-time reverse transcription-polymerase chain reaction.
22181687IL-21 levels were compared between chronic periodontitis and healthy gingival tissues and correlated with cytokine and clinical parameters of tissue destruction.
22181687RESULTS: A significant overexpression of IL-21, IL-1β, IL-6, IL-17, and IL-23p19 was detected in periodontal disease-affected tissues compared to healthy gingival tissues.
22181687IL-21 yielded significant positive correlations with probing depth, clinical attachment level, IL-1β, and IL-6.
22181687In addition, IL-21 was negatively correlated with IL-10 and TGF-β1.
22181687CONCLUSIONS: IL-21 was overexpressed in chronic periodontitis gingival tissues and correlated with clinical parameters of periodontal destruction and with proinflammatory cytokines.
22181687Therefore, IL-21 might play a role in the tissue destruction that characterizes chronic periodontal disease.
22184726Compared with CD90-depleted CCR6(+) memory Th17 cells, CD4(+)CD90(+) cells express higher levels of IL-22 and proinflammatory cytokines (IL-6, TNF-α and GM-CSF), but they produce lower levels of IL-21 and no IL-9.
22188745Furthermore, a certain number of CD4+CXCR5+ICOShigh T cells together with enhanced expression of IL-21 and Bcl-6 mRNA were detected in thyroid tissues from Hashimoto's thyroiditis patients.
22197976Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21.
22222887CD4(+) effector T-cells secrete IL-17, IL-21, and IL-22 in autoimmune and inflammatory disease, and are dynamically balanced with T(REG) cell development.
22226370IL-21 and Sjögren's syndrome.
22226370Interleukin-21 (IL-21) is elevated in the serum of patients with this disease and is expressed by the lymphocytes infiltrating the salivary glands.
22226370The known functions of IL-21 in facilitating differentiation, proliferation, and survival of both B and T cells mesh well with the findings in Sjögren's syndrome.
22226370Demonstration of IL-21 as a fundamental aspect of the pathophysiology of Sjögren's syndrome could lead to the development of anti-IL-21 therapy for this disease.
22230045These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice.
22230045Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice.
22230045Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.
22231702IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice.
22231702MRL/MpJ-Fas(lpr/lpr)/J (MRL(lpr)) mice develop lupus-like disease manifestations in an IL-21-dependent manner.
22231702IL-21 is a pleiotropic cytokine that can influence the activation, differentiation, and expansion of B and T cell effector subsets.
22231702Together, our data highlighted the novel observation that IL-21 is a critical regulator of multiple pathogenic B and T cell effector subsets in MRL(lpr) mice.
22235133IL-21 is a class I cytokine that exerts pleiotropic effects on both innate and adaptive immune responses.
22235133It signals through a heterodimeric receptor complex consisting of the IL-21 receptor (IL-21R) and the common γ-chain.
22235133Here, we present the crystal structure of IL-21 bound to IL-21R and reveal that the WSXWS motif of IL-21R is C-mannosylated at the first tryptophan.
22238455IL-21 can supplement suboptimal Lck-independent MAPK activation in a STAT-3-dependent manner in human CD8(+) T cells.
22238455However, when CD8-independent T cell priming and restimulation were supplemented with IL-21, Ag-specific CD8(+) CTL expanded in two of six individuals tested.
22238455We found that IL-21 rescued partial MAPK activation in a STAT3- but not STAT1-dependent manner.
22238455However, STAT3-mediated IL-21 signaling can supplement partial TCR signaling caused by the lack of CD8 association.
22261234Regulation of CD28 expression on umbilical cord blood and adult peripheral blood CD8+ T cells by interleukin(IL)-15/IL-21.
22261234Interleukin (IL)-15 and IL-21, both belonging to common γ-chain-signaling cytokine family, have an important role to maintain homeostatic proliferation of CD8(+) T cells.
22261234We investigated the effect of IL-15 and IL-21, alone or in combination, on activation, apoptosis, cytokine production and cytotoxic function of magnetic bead purified umbilical cord blood (UCB) and adult peripheral blood (APB) CD8(+) T cells with regards to their CD28 expression.
22261234We established that (1) IL-15-induced CD8(+) T cell proliferation was associated with a preferential expansion of CD28(-) population in UCB, which could be partially counteracted by IL-21; (2) UCB CD8(+) T cells were more readily responsive to IL-15 compared to their adult counterparts in terms of CD69 expression, with the majority of CD69-bearing CD8(+) T cells were CD28(-); (3) IL-21 further promoted interferon-gamma, but not tumor necrosis factor-alpha production from IL-15 treated CD8(+) T cells; (4) IL-21 also synergized with IL-15 to enhance perforin and granzyme B expression of CD8(+) T cells, especially in APB CD8(+)CD28(-) subsets; (5) IL-21 resulted in CD8(+) T cells apoptosis both in APB and UCB cells, mainly in CD8(+)CD28(-) subsets.
22261234Taken together, we demonstrate differential IL-15/IL-21 response in UCB CD8(+) T cells with regards to CD28 expression.
22261234Our results suggest that combining IL-21 and IL-15 immunotherapy may be better than IL-15 alone to ameliorate graft-versus-host disease while preserving antitumor effect in the post-UCB transplantation period.
22292798Abstract Angiogenin (ANG) gene mutations have been identified in both familial and sporadic amyotrophic lateral sclerosis (ALS) patients from multiple European and North American populations.
22292798However, no ANG mutation has yet been reported in Asian ALS populations.
22292798Here, we screened for ANG mutations in a Chinese ALS cohort.
22292798The entire coding region of the ANG gene was sequenced in 10 familial ALS pedigrees, 202 sporadic ALS patients, and 151 healthy controls.
22292798All patients were negative for SOD1, FUS, and TARDBP mutations.
22292798V103I), in one sporadic ALS patient, but not in the controls.
22292798No mutations were found in the familial ALS patients.
22292798We identified the presence of the known single nucleotide polymorphism, rs11701 (T/G), in both ALS cases and controls.
22292798However, no significant association of the G allele with ALS susceptibility was demonstrated.
22292798SOD1-, FUS-, TARDBP- mutation-negative ALS cohort.
22292798Our findings highlight that the genetic background of ALS differs between different populations, and suggest that ANG mutation may be involved in the aetiology of ALS in the Han Chinese population.
22315057IL-21 in combination with cetuximab in patients with metastatic colorectal cancer.
22318729Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification.
22318729We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression.
22340646Ongoing research is also providing significant insights into the target cells and underlying mechanisms of Th17-secreted cytokines, including IL-17A, IL-21 and IL-22.
22345665IL-10 synthesis was stimulated by direct Gal-1 engagement to cell surface glycoproteins, principally CD45, on activated Th cells and enhanced by IL-21 expression through the c-Maf/aryl hydrocarbon receptor pathway, independent of APCs.
22355761To evaluate adoptive immunotherapy treatment for B-lineage non-Hodgkin lymphoma (NHL), we expanded T cells from client-owned canines diagnosed with NHL on artificial antigen presenting cells (aAPC) in the presence of human interleukin (IL)-2 and IL-21.
22356196It seems that IL-21 plays an important role in the pathogenesis of psoriasis.
22356196Therefore, our study focuses on serum IL-21 levels and their correlation with disease severity.
22356196OBJECTIVES: To detect serum IL-21 levels in patients with psoriasis and investigate the correlation between these and the Psoriasis Area and Severity Index (PASI) scores.
22356196Serum IL-21 levels were measured by enzyme-linked immunosorbent assay in 37 patients with psoriasis and 37 healthy controls.
22356196The PASI scores of patients with psoriasis and their correlation with serum IL-21 levels were evaluated.
22356196CONCLUSIONS: Serum IL-21 levels in patients with psoriasis are elevated and positively correlate with PASI scores.
22356196These results indicate that IL-21 may play an important role in the pathogenesis of psoriasis.
22370718In CD4(+) T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation.
22370718Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4(+) T cell IL-21 production and increased IL-21 B cell responsiveness.
22370718We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner.
22399602BACKGROUND/AIM: Interleukin-21(IL-21) stimulates cytotoxicity and interferon-γ (IFN-γ) production in natural killer (NK) cells.
22399602However, little has been reported on the stimulatory effect of IL-21 on ex vivo expanded NK cells.
22399602In this study, we examined the cytotoxicity and IFN-γ production of ex vivo expanded, IL-21-stimulated NK cells against trastuzumab-coated breast cancer cells.
22399602After a 4-day stimulation with IL-21, NK cell cytotoxicity and IFN-γ production were measured.
22399602Cytotoxicity of the expanded NK cells against the MCF-7, SKBR3, and T47D cell lines was significantly increased following 4-day stimulation with IL-21.
22399602IL-21 pre-treatment also increased IFN-γ production in the expanded NK cells in response to the trastuzumab-coated breast cancer cells.
22399602CONCLUSION: IL-21 significantly enhances the cytolytic activity and IFN-γ production of ex vivo expanded NK cells in response to trastuzumab-coated breast cancer cells.
22406425Nanoparticle-based adjuvant for enhanced protective efficacy of DNA vaccine Ag85A-ESAT-6-IL-21 against Mycobacterium tuberculosis infection.
22430249IL-27 induction of IL-21 from human CD8+ T cells induces granzyme B in an autocrine manner.
22430249Interleukin (IL)-27 exerts an anti-inflammatory effect on human and mice CD4(+) T cells by inducing IL-10-producing T regulatory 1 cells through induction of IL-21.
22430249However, the role of IL-27 and how it regulates IL-21 from human CD8(+) T cells is unclear.
22430249Here, we show that the IL-27 receptor is expressed on human CD8(+) T cells and stimulation of human naïve CD8(+) T cells in the presence of IL-27 leads to an increase in IL-21 and interferon (IFN)-γ production.
22430249IL-21 induction in IL-27-stimulated human CD8(+) T cells correlates specifically with expression of the transcription factor T-bet.
22430249IL-27 stimulation of naïve CD8(+) T cells induces a double-positive T-bet(+) IL-21(+) expressing CD8(+) T-cell population.
22430249Antibody-mediated neutralization of IL-21 abrogates IL-27-induced granzyme B expression.
22430249Moreover, direct addition of IL-21 greatly amplifies granzyme B expression in human naïve CD8(+) T cells.
22430249Our findings identify IL-27-induced IL-21 as a key autocrine regulator of granzyme B expression in human CD8(+) T cells.
22434910IL-4, IL-17A, and IL-21 (all P < 0.
22434910IL-21 (P = 0.
22442347IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis.
22442347We have previously shown that the cytokine IL-21 can counteract Treg suppression.
22442347However, whether this reflects an effect of IL-21 on Treg, conventional T cells, or antigen-presenting cells is not known.
22442347Here we have used lymphocyte populations from IL-21R-deficient mice to pinpoint which cell type needs to be targeted by IL-21 for Treg suppression to be overcome.
22442347We show that IL-21 counteracts suppression by acting on conventional T cells and that this is associated with inhibition of IL-2 production.
22442347Despite the lack of IL-2, conventional T-cell responses proceed unimpaired because IL-21 can substitute for IL-2 as a T cell growth factor.
22442347However, IL-21 is unable to substitute for IL-2 in supporting the Treg compartment.
22442347Thus, IL-21 signaling in conventional T cells indirectly impacts Treg homeostasis by decreasing IL-2 availability.
22442347These data demonstrate that IL-21 and IL-2 can have overlapping roles in promoting conventional T-cell responses but play distinct roles in controlling Treg homeostasis and function.
22465422IL-21 is a multi-functional cytokine which can promote survival, proliferation and activation of T and B lymphocytes including CD8 T cells.
22465422To evaluate the role of IL-21 in promoting CD8+ T cell mediated cardiac injury in myocarditis, C57Bl/6 and IL-21RKO mice were infected with CVB3.
22465422Numbers of CD8+IFNγ+ cells were decreased in IL-21RKO mice but numbers of either CD4+IFNγ+ or CD4+IL-4+ cells were not significantly different from C57Bl/6 animals indicating a selective effect of IL-21 signaling on the CD8+ T cell response.
22465422To confirm that IL-21 signaling exclusively functions at the level of the CD8+ T cell in CVB3 induced myocarditis, purified CD8+ cells were isolated from either C57Bl/6 or IL-21RKO donors and adoptively transferred into CD8KO recipients prior to CVB3 infection.
22465422These data demonstrate that IL-21 signaling directly in the CD8+ cell population is required for CVB3-induced myocarditis.
22466669The development and fate of follicular helper T cells defined by an IL-21 reporter mouse.
22466669To track the development and fate of TFH cells, we generated an IL-21 reporter mouse by introducing sequence encoding green fluorescent protein (GFP) into the Il21 locus; these mice had expression of IL-21–GFP in CD4⁺CXCR5⁺PD-1⁺ TFH cells.
22466669IL-21–GFP⁺ TFH cells were multifunctional helper cells that coexpressed several cytokines, including interferon-g (IFN-g), IL-2 and IL-4.
22471280IL-22 receptor (IL-22R) expression is limited to epithelial cells of the digestive organs, respiratory tract and skin.
22471280Like IL-17, high levels of IL-22 have been detected in tumour tissues and the peripheral blood of cancer patients; however, the direct effect of IL-22 on tumour cells has remained largely unknown.
22471280In this report, we show that IL-22 stimulated production of vascular endothelial growth factor (VEGF) and the anti-apoptotic factor Bcl-X(L) in IL-22R-positive HPAFII human pancreatic cancer cells.
22474026Ab(+) versus Ab(-) children (interleukin [IL]-1β, IL-5, IL-7, IL-12(p70), IL-16, IL-17, IL-20, IL-21, IL-28A, tumor necrosis factor-α, chemokine C-C motif ligand [CCL]13, CCL26, chemokine C-X-C motif ligand 5, granulocyte-macrophage colony-stimulating factor, and thrombopoietin); most have proinflammatory effects.
22474026IL-21 was lower (P = 0.
22474026Apart from differences in IL-10 and IL-21, EV infection was not associated with a specific cytokine profile.
22486304Interleukin-21 (IL-21) is a T-cell-derived cytokine that modulates T-cell, B-cell, and natural killer cell responses.
22486304We found that a higher level of antigen-specific cytotoxic responses was induced in BALB/C mice immunized with pGX-EnvC with the pVAX-IL-21 via electroporation.
22486304The plasma cell inhibitory transcription factors B-cell lymphoma 6 protein (Bcl-6) and Pax-5 were increased in B cells from mice that had been immunized by HIV DNA vaccine plus pVAX-IL-21, suggesting that the expressed IL-21 may inhibit the differentiation from B cells to plasma cells.
22486304These results indicate that IL-21 could enhance CD8⁺ T-cell immunity, but inhibit humoral responses during HIV DNA vaccination.
22490633IL-21 mainly expressed in heart and spleen, IL-21R, IL-17, TGF-β mainly expressed in spleen, and IL-17, IL-6 mainly expressed in heart of EAM rats.
22490633In line with pathological EAM course, the expression of IL-21 and related cytokines peaked at 2 weeks and then returned to normal at 4 weeks after immunization.
22490633CONCLUSION: IL-21 and related cytokines were involved in the pathological process of EAM, upregulated IL-21 expression might promote Th17 cell differentiation and enhance Th17 cell secretion.
22491065IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells.
22491065Deciphering the signals that induce IL-21 production in CD4(+) T cells and those triggered by IL-21 in B cells are, therefore, of importance for understanding the generation of antibody (Ab) responses.
22491065Here, we show that IL-6 increased IL-21 production by human CD4(+) T cells, particularly in those that express the transcriptional regulator B cell lymphoma (BCL)6, which is required in mice for the development of C-X-C chemokine receptor type 5 (CXCR5(+)) IL-21-producing T follicular helper (T(FH)) cells.
22491065We show here that IL-21 was required for the induction of Ab production by IL-6.
22491065In IL-21-treated B cells, signal transducer and activator of transcription (STAT)3 was required for optimal immunoglobulin production and upregulation of PR domain containing 1 (PRDM1(+)), the master plasma cell factor.
22491065These results, therefore, demonstrate the critical importance of STAT3 activation in B cells during IL-21-driven humoral immunity and suggest that BCL6 expression, although not sufficient, may serve as a platform for the acquisition of a T(FH)-like phenotype by human CD4(+) T cells.
22493728Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis.
22493728BACKGROUND: Amyotrophic lateral sclerosis (ALS) is incurable and characterized by progressive paralysis of the muscles of the limbs, speech and swallowing, and respiration due to the progressive degeneration of voluntary motor neurons.
22493728Clinically indistinguishable ALS can be caused by genetic mutations of Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein 43 (TDP43), or fused in sarcoma/translocated in liposarcoma (FUS/TLS), or can occur in the absence of known mutation as sporadic disease.
22493728In this study, we tested the hypothesis that FUS/TLS and TDP43 gain new pathogenic functions upon aberrant accumulation in the cytosol that directly or indirectly include misfolding of SOD1.
22493728METHODOLOGY/PRINCIPAL FINDINGS: Patient spinal cord necropsy immunohistochemistry with SOD1 misfolding-specific antibodies revealed misfolded SOD1 in perikarya and motor axons of SOD1-familial ALS (SOD1-FALS), and in motor axons of R521C-FUS FALS and sporadic ALS (SALS) with cytoplasmic TDP43 inclusions.
22493728SOD1 misfolding and oxidation was also detected using immunocytochemistry and quantitative immunoprecipitation of human neuroblastoma SH-SY5Y cells as well as cultured murine spinal neural cells transgenic for human wtSOD1, which were transiently transfected with human cytosolic mutant FUS or TDP43, or wtTDP43.
22493728The lack of immunohistochemical compartmental co-localization of misfolded SOD1 with cytosolic TDP43 or FUS suggests an indirect induction of SOD1 misfolding followed by propagation through template directed misfolding beyond its site of inception.
22493728The identification of a final common pathway in the molecular pathogenesis of ALS provides a treatment target for this devastating disease.
22508526IL)-12, IL-21, IL-27, or IL-33 will lead to a better clinical response than with anti-TNF-α antibodies.
22526020Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6.
22526020In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases.
22532637Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort.
22532637METHODS: Serum interleukin (IL)-1β, IL-1 receptor antagonist (IL1-Ra), IL-2, IL-4, IL-6, IL-10, IL-17, IL-21, monocyte chemotactic protein 1 (MCP-1), tumour necrosis factor α and interferon γ levels were measured in the (ESPOIR) Etude et Suivi des POlyarthrites Indifférenciées Récentes early arthritis cohort, which included patients with at least two swollen joints for >6 weeks and <6 months, and no previous corticosteroids or disease-modifying antirheumatic drugs.
22532637RESULTS: Serum IL-6 and IL-21 were the only cytokines that discriminated RA from UA on univariate analysis.
22532637Higher proportions of rheumatoid factor and anticyclic citrullinated protein (CCP) positivity, levels of markers of B cell activation, and a higher frequency of rapid radiographic progression were observed in patients with RA with detectable IL-6 or IL-21.
22533549Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, plays a major role in the control of innate and adaptive immune responses.
22533549IL-21 biological activity is mediated by binding of the cytokine to a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R), and the common γ-chain, that is shared with IL-2, IL-4, IL-7, IL-9 and IL-15 receptors.
22533549IL-21 stimulates the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, and enhances the activity of natural killer cells.
22533549IL-21 controls also the activity of non-immune cells, such as epithelial cells and stromal cells.
22533549The demonstration that IL-21 is involved in the immune responses occurring in chronic inflammatory and allergic diseases suggests that either disrupting or enhancing IL-21 signalling may be useful in specific clinical settings.
22544947Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease.
22544947The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects.
22547705We show that Th2i cells develop directly from Th2 effectors, in a manner that can be promoted by effector cytokines including IL-2, IL-10, and IL-21 ex vivo and that requires T cell activation through CD28, Card11, and IL-2 in vivo.
22563406TDP-43 identified from a genome wide RNAi screen for SOD1 regulators.
22563406Amyotrophic Lateral Sclerosis (ALS) is a late-onset, progressive neurodegenerative disease affecting motor neurons in the brain stem and spinal cord leading to loss of voluntary muscular function and ultimately, death due to respiratory failure.
22563406ALS cases are familial and associated with mutations in superoxide dismutase 1 (SOD1) that destabilize the protein and predispose it to aggregation.
22563406In spite of the fact that sporadic and familial forms of ALS share many common patho-physiological features, the mechanistic relationship between SOD1-associated and sporadic forms of the disease if any, is not well understood.
22563406Biochemical experiments confirmed the action of TDP-43 on SOD1.
22563406These results highlight an unexpected relationship between TDP-43 and SOD1 which may have implications in disease pathogenesis.
22575358TAR DNA-binding protein (TARDBP) mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations.
22575358Here, we sequenced the coding region of all five TARDBP exons for mutations in 13 familial ALS (FALS) pedigrees and 312 sporadic ALS (SALS) patients of Chinese origin, as well as 245 healthy control subjects.
22575358Japanese and lower than White populations, whereas the estimated mutation frequency in superoxide dismutase 1 (SOD1)-negative FALS patients (15.
22575358Our findings provide an overview of the occurrence of TARDBP mutations in Chinese ALS patients and highlight the importance of TARDBP mutation screening in Chinese ALS patients.
22621957METHODS: Methods used include clinical review; Sanger DNA sequencing of the SP110 gene; determination of transfected mutant protein function by using immunofluorescent studies in Hep-2 cells; quantitation of B-cell subsets by means of flow cytometry; assessments of B-cell function after stimulation with CD40 ligand, IL-21, or both; and differential gene expression array studies of EBV-transformed B cells.
22634616IL-21 is an important regulator of plasma cell differentiation, and it controls the master regulator of plasma cell differentiation, B lymphocyte-induced maturation protein-1 (BLIMP-1), via STAT3 and IRF4.
22634616In contrast to the induction of miR-21 observed in response to STAT3 activation in other systems, we demonstrate that miR-21 is repressed during IL-21-driven plasma cell differentiation.
22634616Thus, STAT3 and BLIMP-1 constitute an incoherent feed-forward loop downstream of IL-21 that can coordinate microRNA with mRNA expression during plasma cell differentiation.
22640807Transforming growth factor-β and inflammatory cytokines, such as IL-6, IL-21, IL-1β, and IL-23, play central roles in the generation of Th17 cells.
22640807However, under certain conditions, these cells and their effector molecules, such as IL-17, IL-21, IL-22, GM-CSF, and CCL20, are associated with the pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease, and allergy and asthma.
22645277Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component.
22645277In five of the FALS families, we identified multiple mutations in ALS-associated genes.
22645277We detected FUS/TLS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP, SOD1 and FUS/TLS mutations.
22645277This may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of unaffected family members.
22652779IL)-23, transforming growth factor-beta (TGF-beta), IL-1beta, IL-6, IL-17, IL-22, and IL-21, have been shown related to Th17 cells.
22699059OBJECTIVE: To develop a novel vaccine by immobilizing interleukin-21 (IL-21) on the surface of MB49 cells and evaluate its effect in inducing specific cytotoxic T lymphocytes (CTLs) and antitumor immunity in a mouse model of subcutaneous metastatic bladder cancer.
22699059METHODS: SA-IL-21 was immobilized on the surface of 30% ethanol-fixed MB49 cells to prepare the cell vaccine.
22699059RESULTS: IL-21 surface-modified MB49 cell vaccine significantly inhibited the tumor growth and generated a long-lasting memory response (P<0.
22699059At the same effector-target (E:T) ratio, the specific CTLs induced by IL-21/MB49 vaccine showed the most potent cytotoxicity against MB49 cells (P<0.
22699059CONCLUSION: With the protein-anchor technique, IL-21 can be efficiently immobilized on the surface of MB49 cells to prepare IL-21/MB49 cells vaccine.
22701882In this study, we sequenced 4 small RNA libraries from one inactivated and three activated human NK cells treated with cytokines interleukin-2 (IL-2), IL-15 and IL-21, respectively, by using the Illumina high-throughput sequencing technology.
22701882We identified a total of 440, 458, 475 and 452 known mature miRNAs in resting and IL-2, IL-15 and IL-21 activated human NK cells, respectively.
22701882This is the first time we showed the microRNA transcriptomes and differentially expressed miRNAs involved in human NK cell activation by IL-2, IL-15 and IL-21 stimulation, which provides valuable clues for the further elucidation of microRNA regulation in human NK cell activation and may have a great potential in NK cell immunotherapy.
22705151ICAM-1, IL-21 and IL-23 in patients with tick borne encephalitis and neuroborreliosis.
22705151ELISA kits (DRG Instruments, Germany) were used to measure the concentration of IL-21, IL-23 and sICAM-1.
22705151In TBE, a strong negative correlation between CSF concentration of IL-21 and IL-23 and monocyte count in CSF was observed.
22705151Negative correlation between IL-21 in CSF and neutrophil count was also noted.
22705151In NB, a strong positive correlation between serum IL-21 and platelet count and negative correlation between IL-21 in serum and CSF with pleocytosis was observed.
22712263Produce IL-17A, IL-17F, IL-21, IL-22, IL-26, IL-6, TNF-alpha.
22720235Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNγ, IL-12, IL-21 and costimulation.
22723515Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models.
22723515Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described.
22739232Here, we investigated the production of pro-constructive cytokine, Interleukin-22 (IL-22), in the bronchoalveolar lavage (BAL), trachea, lung tissue, and spleen during influenza infection.
22739232Tracheal epithelial cells constitutively expressed high levels of IL-22R and underwent active proliferation in response to IL-22 in the wild-type mice.
22739232Adoptive transfer of IL-22-sufficient but not IL-22-deficient NK cells into IL-22(-/-) mice restored the tracheal/bronchial epithelial cell regeneration and conferred protection against inflammation.
22753386Recent studies have reported that IL-21 is involved in the formation of germinal centres (GCs) and class switching of IgG4.
22753386In this study the expression of IL-21 in IgG4-DS and SS patients was examined.
22753386METHODS: Twelve patients with IgG4-DS, 15 with SS and 15 healthy subjects were screened for (1) ectopic GC formation in formalin-fixed labial salivary gland (LSG) biopsy samples; (2) expression of IL-21, Th2-, Th17- and Tfh-related molecules (cytokines, chemokine receptors and transcription factors) in LSGs; (3) relationship between IgG4/IgG ratio and mRNA expression of IL-21 in LSGs.
22753386RESULTS: mRNA expression of IL-21 and Bcl-6 in LSGs from patients with IgG4-DS was significantly higher than in patients with SS and controls.
22753950Specifically, Th17 cells produce effector cytokines IL-17, IL-21, and IL-22 under the regulation of ROR-γt.
22754778In our recent manuscript we have revealed that the Th17 associated cytokine IL-21 prominently influences tumor development and immunosurveillance of colitis-associated colorectal cancer.
22763176Secretion of IL-21 is restricted mainly to T follicular helper (TFH) CD4 T cell subset with contributions from Th17, natural killer (NK) T cells, but the effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor.
22763176The role of IL-21 in sustaining and regulating T cell, B cell and NK cell responses during chronic viral infections has recently come into focus.
22763176This chapter reviews current knowledge about the biology of IL-21 in the context of HIV infection.
22770960NK cells from normal donors were treated overnight with IL-2 (100 U), IL-12, IL-15, or IL-21 (all 10 ng/mL) and tested for ADCC versus cetuximab-coated cancer cells in a 4 hr (51)Cr assay.
22785229IL-15 positively regulates IL-21 production in celiac disease mucosa.
22785229Celiac disease (CD)-associated inflammation is characterized by high interleukin- 21 (IL-21), but the mechanisms that control IL-21 production are not fully understood.
22785229IL-21-producing cells coexpressed interferon-γ (IFN-γ) and to a lesser extent T helper type 17 (Th17) cytokines.
22785229Treatment of control LPLs with IL-15, a cytokine overproduced in CD, activated Akt and STAT3 (signal transducer and activator of transcription 3), thus enhancing IL-21 synthesis.
22785229Active CD biopsies contained elevated levels of Akt, and blockade of IL-15 in those samples reduced IL-21.
22785229Similarly, neutralization of IL-15 in biopsies of inactive CD patients inhibited peptic-tryptic digest of gliadin-induced IL-21 expression.
22785229These findings indicate that in CD, IL-15 positively regulates IL-21 production.
22792085Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation.
22805136Among these cytokines, Interleukin-21 (IL-21) is a relatively recently discovered cytokine, which is mainly produced by CD4(+) T cells in the body, and exerts multiple and pleiotropic effects on various immune cells.
22819243TWEAK promoted IL-17 production synergistically with IL-23 or IL-21 and blockade of Fn14 with Fn14-Fc suppressed Th17 differentiation.
22847232The phenotype of pXZ12-RORγt transduced cells in the presence of TGF-β and IL-6 was similar to natural Th17 cells, in contrast to cells overexpressing RORγt alone which were deficient for IL-21.
22849297ELISA analysis showed that the refolded rhIL-21R-ECD bound to its ligand IL-21 in a concentration-dependent manner.
22849333Plasma IL-21, a cytokine important for B-cell development and antibody synthesis, was also lower in COPD patients who had an AECOPD, than in stable COPD patients (p = 0.
22859347Interleukin 21 (IL-21) plays a critical role in T cell and B cell homeostasis.
22859347Analysis of CD4+ T cells producing IL-21, Th1, Th2, Th17, Treg, follicular helper T (TFH) cells, and B cells was performed in peripheral blood, and levels of cytokines were measured in culture supernatants.
22859347RESULTS: Circulating CD4+ T cells producing IL-21 were markedly expanded in patients with SLE compared to controls and were correlated with increased Th17, decreased Treg, and increased memory B cells.
22859347CD4+ T cells producing IL-21 were composed of CXCR5+ and CXCR5-CD4+ T cell subsets.
22859347Both IL-21-producing CXCR5+CD4+ T cells and CXCR5-CD4+ T cells were increased in patients with SLE, the CXCR5-CD4+ subset correlating with Th17 cells and Treg, while the CXCR5+CD4+ subset was correlated with alterations of the B cell subset.
22859347CONCLUSION: These findings suggest that IL-21, produced by distinct cellular CD4+ T cells, correlates with alterations of T cell and B cell subsets in SLE, and that targeting IL-21 could provide beneficial effects on both T cell and B cell alterations.
22860700We analysed the expression and localization of familial ALS-causing proteins, including transactive response DNA binding protein-43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), Cu/Zn superoxide dismutase (SOD1) and optineurin (OPTN) by immunohistochemistry.
22860700RESULTS: TDP-43, OPTN and, to a lesser extent, FUS/TLS were more frequently accumulated in the cytoplasm in patients with sIBM and OPMD than in patients with PM, DM, neurogenic muscular atrophy, or healthy control subjects.
22860700Confocal microscopy imaging showed that TDP-43 proteins more often colocalized with OPTN than with FUS/TLS, p62 and phosphorylated Tau.
22886969Th17 associated cytokines, IL-6, IL-21 and IL-22, were also increased significantly at 72 h post-infection.
22890575Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions.
22898872Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice.
22898872Pathological features of amyotrophic lateral sclerosis (ALS) include, in addition to selective motor neuron (MN) degeneration, the occurrence of protein aggregates, mitochondrial dysfunction and astrogliosis.
22898872SOD1 mutations cause rare familial forms of ALS and have provided the most widely studied animal models.
22898872Relatively recent studies implicating another protein, TDP-43, in familial and sporadic forms of ALS have led to the development of new animal models.
22898872More recently, mutations in the valosin-containing protein (VCP) gene linked to the human genetic disease, Inclusion Body Myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD), were found also to be associated with ALS in some patients.
22898872Although these animals do not develop rapidly progressive fatal ALS-like disease during their lifespans, they recapitulate key pathological features of both human disease and other animal models of ALS, and may provide a valuable new model for studying events preceding onset of catastrophic disease.
22915661PATIENTS AND METHODS: Patients with no prior systemic therapy and with limited-disease MM were treated with IL-21 by using three different dosing regimens.
22915661ORR did not appear to depended on IL-21 receptor expression or BRAF mutation status.
22915661CONCLUSION: The ORR to IL-21 is 22.
22921334IL-6 induces IL-21 production in CD4 T cells and IL-10-inducing effect of IL-6 requires both IL-21 and IL-2.
22921334Although IL-6 cannot induce IL-10 production in CD8 T cells in a cell-autonomous manner, it can do so indirectly through promoting CD4 T cell IL-21 production.
22922411Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons.
22922411Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans.
22922411Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4.
22922411In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival.
22922411Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy.
22922995Conversely, STAT3 suppression by STAT3 siRNA strongly disrupted the downregulation of these genes by IL-22, but it did not significantly affect the activation of ERK1/2 by IL-22.
22930805Infected macrophages were also analyzed for expression of interleukin 21 (IL-21) and negative regulators of immune responses.
22930805MAC triggered expression of IL-21, IRF4, and STAT3 genes related to IL-17 regulation, as well as expression of the negative immunoregulators CD274(PD-L1) and suppressors of cytokine signaling.
22933251Seven available minor salivary gland (MSG) tissue specimens from patients in the primary SS cohort were also assessed for interferon-α (IFNα), BAFF, and interleukin-21 (IL-21) cytokine transcripts, which are all implicated in B cell activation.
22933251OH) antibodies and expression of IFNα, BAFF, and IL-21 messenger RNA in MSG tissues was also detected.
22941224Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism.
22941224While the pathogenesis of amyotrophic lateral sclerosis (ALS) remains to be clearly delineated, there is mounting evidence that altered RNA metabolism is a commonality amongst several of the known genetic variants of the disease.
22941224We observed that RGNEF-immunoreactive neuronal cytoplasmic inclusions (NCIs) can co-localize with TDP-43, FUS/TLS and p62 within spinal MNs.
22941224We also found that mtSOD1-ALS cases possess a unique IHC signature, including the presence of C9orf72-immunoreactive diffuse NCIs, which allows them to be distinguished from other variants of ALS at the level of light microscopy.
22964832SUBJECTS We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation.
22964832ALS, 5.
22964832Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions.
22976953IL-21 in the bone marrow microenvironment contributes to IgM secretion and proliferation of malignant cells in Waldenstrom macroglobulinemia.
22976953One such cytokine, IL-21, promotes the growth of myeloma and Hodgkin lymphoma cells while inducing apoptosis in chronic lymphocytic leukemia.
22976953However, the biologic significance of IL-21 has not been examined in Waldenstrom macroglobulinemia (WM), a B-cell lymphoma characterized by elevated serum IgM and a lymphoplasmacytic bone marrow infiltrate.
22976953We report here on the presence of IL-21 in the bone marrow of patients with WM and have identified activated T cells as the source of this cytokine.
22976953We readily detected the IL-21 receptor on malignant WM B cells and show that IL-21 significantly increases both IgM secretion and cellular proliferation of these cells with no effect on viability.
22976953IL-21 rapidly induces phosphorylation of STAT3 in WM cells, and treatment of the WM cell line MWCL-1 with a STAT3 inhibitor abolished the IL-21-mediated increases in cellular proliferation and IgM secretion.
22976953IL-21 also increased the expression of known STAT3 targets involved in B-cell differentiation, including BLIMP-1, XBP-1, IL-6, and IL-10.
22976953Overall, our data indicate that IL-21 in the bone marrow microenvironment significantly affects the biology of WM tumor cells through a STAT3-dependent mechanism.
22985564OBJECTIVE: To detect serum interleukin-21 (IL-21) levels in patients with chronic hepatitis B receiving different therapeutic regimens.
22985564IL-21 and serum hepatitis B virus (HBV) markers were detected in these patients using enzyme-linked immunosorbent assay (ELISA), and the liver function indices were measured with an auto-biochemical analyzer.
22985564RESULTS: The serum IL-21 levels in Con and IFN groups were significantly higher than those in NA group (102.
22985564When all the patients were regrouped according to the status of HBeAg, serum IL-21 level was 114.
22985564Bivariate correlation analysis showed no significant correlations between IL-21 and liver function indices.
22985564HBeAg-negative patients have a significantly higher serum IL-21 level, suggesting that the expression of HBeAg might result in IL-21 depression.
22992523Moreover, BATF-JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4(+) T cells stimulated with IL-21 and in T(H)17 differentiated cells.
22992523Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in T(H)17 cells and potently regulated by IL-21.
22994784The concentration of IL-21 in MPE was significantly higher compared to TPE (P<0.
22994784IL-21 had a sensitivity of 76.
22994784Combined detection of IL-21 and CEA had a sensitivity of 69.
22999566We report a patient with sporadic amyotrophic lateral sclerosis (ALS) with a novel fusion in malignant liposarcoma (FUS) gene mutation whose neurological signs were conspicuous left-sided rigidity and apraxia.
22999566Re-sequencing of the genes for superoxide dismutase 1 (SOD1) and transactive response-DNA binding protein (TARDBP) revealed no mutations.
22999566Met464Ile) is related to manifestations of ALS as well as clinical features of corticobasal degeneration.
23000427In addition, the expression of Akt1, cyclin D1, and IL-21 mRNA was significantly increased during MS relapses when compared to levels in healthy controls.
23034328Expression of the nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NKFB1), transforming growth factor (TGF)-β (TGFB), IFN-γ-inducible protein 16 (IFI16) and IL-21 (IL21) genes was higher in viable than retarded heifers.
23050732BACKGROUND: Recently, a new subset of T helper (Th) cell that predominantly secret cytokine interleukin-22 (IL-22) is identified, termed Th22 cells.
23050732On day 14 post injection, frequencies of splenic Th22 cells were determined, productions of IL-22 and expressions of IL-22R (IL-22 receptor) were measured.
23050732To further investigate the effects of IL-22, AVMC mice treated with Anti-IL-22 neutralizing antibody were explored.
23050732The severity of AVMC were monitored; the frequencies of Th22 cells, the expressions of IL-22 and IL-22R were investigated; in addition to IFN-γ, inflammatory cytokines IL-17, TNF-α, IL-6 as well as IL-1β, were evaluated.
23050732RESULTS: Compared with control group, significant elevations of circulating Th22 cells and IL-22, cardiac protein and mRNA of IL-22, and IL-22R1 were demonstrated in AVMC group.
23050732Anti-IL-22 Ab decreased the frequencies of Th22 cells and the levels of IL-22, and increased the expressions of cardiac IL-22R1.
23064231Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.
23064231Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells.
23064231Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease.
23069584Moreover, administration of PG suppressed the expression of IL-6, IL-21, IL-23 receptor and retinoic acid-related orphan receptor γt and enhanced the expression of Foxp3 in both draining lymph nodes and spinal cords.
23072563Serum IL-8 was elevated in 90 HCC patients compared to 180 cirrhotic controls, whereas IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, and VEGF were similar.
23076801We report that simvastatin inhibits IL-1β, IL-23, TGF-β, IL-21, IL-12p70, and induces IL-27 secretion from DCs in RRMS patients, providing an inhibitory cytokine milieu for Th17 and Th1-cell differentiation.
23078282Many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) are linked to the accumulation of specific protein aggregates in affected regions of the nervous system.
23078282SOD1, TDP-43, FUS and optineurin (OPTN) proteins were identified to form intraneuronal inclusions in ALS patients.
23078282In addition, mutations in OPTN are associated with both ALS and glaucoma.
23078282This study generates a mechanistic framework for investigating how OPTN may trigger pathological changes in ALS and other OPTN-linked neurodegenerative disorders.
23114581Protein and mRNA levels of IL-23, IL-17, and other Th17 effector cytokines, such as IL-21 and IL-22, are elevated in areas with active Crohn's disease-related inflammation, whereas lamina propria mononuclear cells from patients with Crohn's disease secrete increased amounts of IL-17 upon T-cell receptor-specific stimulation.
23116218DKO had lower levels of interleukin (IL)-17A, transforming growth-factor (TGF)-β1, IL-21, and CCL20, and higher IL-1β and IL-13 mRNA transcripts in the LG than in the parental CD25KO strain.
23117491BACKGROUND: Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described.
23117491To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy.
23117491C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.
23117491C9N ALS (3.
23137515METHODS: IL-21 and IL-21 receptor (IL-21R) expression was assessed by real-time PCR and flow cytometry in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls.
23137515PBMCs, purified CD19+CD27- naïve and CD19+CD27+ memory B cells were stimulated with IL-21 and CpG-ODN2006 (TLR-9 agonist) to examine generation of memory and plasma (CD19+CD38highIgD-) B cells.
23137515RESULTS: Active SLE patients had 4-fold higher IL-21 mRNA and increased levels of intracellular IL-21 in peripheral blood CD4+ T cells (mean±SD fluorescence intensity, 1.
23137515Stimulation of PBMCs with IL-21 increased the proportion of memory and plasma cells; addition of CpG-ODN2006 enhanced these effects.
23137515Both naïve and memory B cells responded to IL-21/TLR-9 by increased generation of memory and plasma B cells, respectively; an anti-apoptotic effect was observed.
23137515In active SLE, PBMCs stimulation with IL-21 and/or CpG-ODN increased memory and plasma B cells, comparable to healthy controls.
23137515Fc to block IL-21/IL-21R interaction reduced the proportion of plasma cells.
23137515CONCLUSIONS: Increased IL-21 may synergise with TLR-9 signalling and contributes to generation of plasma cells in active SLE patients.
23155438Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity.
23155438PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands.
23155438ALS (2.
23159638Whereas enhanced Th17 response and related molecules such as interleukin (IL)-17, IL-21, IL-22, IL-23 and STAT3 accompanied tumor induction and progression, finding that tumor growth/stage was negatively correlated with increased infiltration of Th17 cells in the tumor mass has prompted elucidation of various antitumor mechanisms elicited by Th17 and their related molecules.
23166761The HF-FO diet improved the obese phenotype by reducing i) serum hormone concentrations (leptin and resistin), ii) adipose tissue mRNA expression of inflammatory cytokines (MCP-1, IFNγ, IL-6, IL17F and IL-21) and iii) total (F4/80⁺ CD11b⁺) and inflammatory adipose tissue M1 (F4/80⁺ CD11c⁺) macrophage content compared to HF (P<0.
23166761In addition, the HF-FO diet reduced both colitis-associated disease severity and colonic mRNA expression of the Th17 cell master transcription factor (RORγτ) and critical cytokines (IL-6, IL-17A, IL-17F, IL-21, IL-23 and IFNγ) versus HF (P<0.
23168836Endogenous IL-21 regulates pathogenic mucosal CD4 T-cell responses during enhanced RSV disease in mice.
23168836IL-21) has recently been found in several diseases, but contribution to mucosal defences has not been described.
23168836In BALB/c mice infected with respiratory syncytial virus (RSV), IL-21 depletion had little effect in primary infection.
23168836Adoptive transfer of splenic CD4 T cells from depleted mice into naive recipients replicated these effects, indicating that IL-21 mediates its effects via CD4 T cells.
23168836Endogenous IL-21, therefore, has potent and specific effects on mucosal antiviral responses, assisting viral clearance, regulating pulmonary T- and B-cell responses, and inhibiting IL-17 production.
23169140IL-21 promotes the production of anti-DNA IgG but is dispensable for kidney damage in lyn-/- mice.
23169140IL-21 is associated with autoimmunity in mice and humans and promotes B-cell differentiation and class switching.
23169140Here, we explore the role of IL-21 in the autoimmune phenotypes of lyn(-/-) mice.
23169140While IL-21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn(-/-) mice, it is required for anti-DNA IgG antibodies and some aspects of T-cell activation.
23169140Surprisingly, GN still develops in lyn(-/-) IL-21(-/-) mice.
23169140These studies identify a specific role for IL-21 in the class switching of anti-DNA B cells and demonstrate that neither IL-21 nor anti-DNA IgG is required for kidney damage in lyn(-/-) mice.
23172754Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility.
23172754OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions.
23172754CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc.
23172754Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
23215754We hypothesized that the decrease of interleukin-21 (IL-21) levels would lead to alterations in survival of elevated immune activation with disease progress.
23215754The serum IL-21 concentrations and the levels of expression of CD38, HLA-DR, and IL-21 receptor in CD8 T cells were detected by flow cytometry.
23215754The percentages of both CD38 and HLA-DR cells in CD8 T cells were significantly inversely related to the serum IL-21 levels.
23215754IL-21 plays an important role in the mechanism of elevated CD8+ T cell immune activation leading to poor outcome in HIV-1 pathogenesis, which will be helpful for the development of current and future anti-HIV strategies.
23216912Increased production of IL-17A in neutropenic mice coincided with increased IL-6 and CXCL1, but not Th17 inducing cytokines TGF-β, IL-21 and IL-23.
23224786Circulating IL-21 levels increase during early simian-human immunodeficiency virus infection in macaques.
23224786The cytokine interleukin-21 (IL-21) regulates viral pathogenesis in individuals infected with human and simian immunodeficiency viruses.
23224786However, because the time of initial infection with HIV in humans is rarely known, the dynamics of IL-21 production during the first weeks have not been adequately explored.
23224786Twenty-two rhesus macaques were infected rectally with simian-human immunodeficiency virus (SHIV)-1157ipd3N4, and for 12 weeks, replication of the virus, the numbers of CD4+ and CD8+ T cells, and the levels of plasma IL-21 were monitored.
23224786Our study demonstrated that plasma levels of IL-21 increased during the early phase of SHIV infection when compared with the values observed before inoculation.
23226194Differential capacity of human skin dendritic cells to polarize CD4+ T cells into IL-17, IL-21 and IL-22 producing cells.
23226194Accumulating evidence suggests a contribution of T cell-derived IL-17, IL-21 and IL-22 cytokines in skin immune homeostasis as well as inflammatory disorders.
23226194In contrast, LCs and CD1c(+)CD14(-)DDCs were able to differentiate naïve CD4(+)T lymphocytes into IL-22 and IL-21-secreting cells, LCs being the most efficient in this process.
23226194Intracellular cytokine staining showed that the majority of IL-21 or IL-22 secreting CD4(+)T lymphocytes did not co-synthesized IFN-γ, IL-4 or IL-17.
23226194IL-21 and IL-22 production were dependent on the B7/CD28 co-stimulatory pathway and ICOS-L expression on skin LCs significantly reduced IL-21 level.
23226194Finally, we found that TGF-β strongly down-regulates both IL-21 and IL-22 secretion by allogeneic CD4(+) T cells.
23228179AIMS: Five to 10% of cases of amyotrophic lateral sclerosis are familial, with the most common genetic causes being mutations in the C9ORF72, SOD1, TARDBP and FUS genes.
23255900Synergistic effects of soluble PD-1 and IL-21 on antitumor immunity against H22 murine hepatocellular carcinoma.
23255900Previous studies have demonstrated that interleukin 21 (IL-21) is a promising cytokine for cancer immunotherapy due to its ability to induce the immunity of T cells and natural killer cells, whereas blockade of the interaction of programmed death receptor-1 (PD-1) with its ligand (PD-L1) reduces peripheral tolerance.
23255900In the current study, we investigated IL-21 alone and in combination with soluble PD-1 (sPD-1) for the treatment of experimental H22 murine hepatocarcinoma.
23255900In these assays, sPD-1 combined with IL-21 was found to significantly inhibit the growth of the tumors in mice.
23255900Combined treatment with IL-21 and sPD-1 enhanced the antitumor immune response compared with that induced by IL-21 alone.
23255900Thus, immunotherapy with IL-21 in combination with sPD-1 was found to induce a more efficacious antitumor immune response, which may have potential clinical implications.
23274784Interleukin-17A (IL-17A) and interleukin-22 (IL-22), mainly secreted by interleukin-17-producing T help cells (Th17), are pleiotropic cytokines that regulate the biological responses of several target cells, including hepatocytes.
23274784IL-22 and anti-human IL-22 receptor (IL-22R) antibody did not change any indexes.
23301223Similarly, the levels of IL-17, IL-21, and IL-23 were detected in a significantly higher proportion of RA patients than OA patients and the frequencies of detectable IL-6, IL-17, and IL-21 were higher in active RA than in inactive RA group.
23319833Th17 cell enhances CD8 T-cell cytotoxicity via IL-21 production in emphysema mice.
23319833In the current study, we tested the protein levels of IL-17 and IL-21 in peripheral blood and lung tissues from cigarette-smoke- (CS-) exposed mice and air-exposed mice, analyzed the frequencies of CD4(+)IL-17(+)(Th17) cells, IL-21(+)Th17 cells, and CD8(+)IL-21R(+) T cells in peripheral blood and lung tissues of mice, and their relationship with emphysematous lesions, and explored the impact of IL-21 on cytotoxic CD8(+) T cells function in vitro.
23319833It was found that the frequencies of Th17, IL-21(+)Th17, and CD8(+)IL-21R(+) T cells and the levels of IL-17 and IL-21 of CS-exposed mice were much higher than those of the air-exposed mice and correlated with emphysematous lesions.
23319833Additionally, the number of IL-21(+)Th17 cells positively correlated with the number of CD8(+)IL-21R(+) T cells.
23319833The in vitro experiments showed that IL-21 significantly augmented the secretion of perforin and granzyme B in CD8(+) T cells from CS-exposed mice.
23320755Overexpression of BTBD10 (BTB/POZ domain-containing protein 10) suppresses G93A-superoxide dismutase 1 (SOD1)-induced motor neuron death in a cell-based amyotrophic lateral sclerosis (ALS) model.
23320755In the present study, paraffin sections of spinal cords from 13 patients with sporadic ALS and 10 with non-ALS disorders were immunostained using a polyclonal anti-BTBD10 antibody.
23320755Reduced BTBD10 expression in the anterior horn cells was more frequent in spinal cords from ALS patients than in cords from patients with non-ALS disorders.
23320755Mirror sections of spinal cords from five sporadic ALS cases were immunostained with antibodies against BTBD10 and trans-Golgi-network (TGN)-46 or pTDP-43.
23326479DON also induced genes related to the pathogenic Th17 cells subset such as IL-23A, IL-22 and IL-21 and not genes related to the regulatory Th17 cells (rTh17) such as TGF-β and IL-10.
23334981Expression of IL-22 and its receptor (IL-22R) in lymphoid organ and target tissues was determined during various phases of arthritis.
23334981RESULTS: IL-22 and IL-22R were up-regulated in lymphoid organs and joints during the course of arthritis.
23354321IL21 and IL21R polymorphisms and their interactive effects on serum IL-21 and IgE levels in patients with chronic hepatitis B virus infection.
23354321This study explored IL21rs907715 and rs2221903 and IL21R T-83C and rs3093301 polymorphisms and serum IL-21 and IgE levels in 395 patients with chronic HBV infection, 75 HBV infection resolvers and 174 healthy controls.
23354321The carriage of IL21 rs2221903 AG/IL21R rs3093301 CT+IL21 rs2221903 AG/IL21R rs3093301 TT was less frequent in patients than in resolvers (pc=0.
23354321IL21 rs2221903 was, by interaction with IL21R rs3093301, associated with serum IL-21 and IgE levels in HBV patients.
23354321It is suggested that IL21 rs2221903 and IL21R rs3093301 polymorphisms may, independently or interactively, affect the susceptibility to and/or persistence of HBV infection potentially through altering IL-21 and IgE production.
23364893EBV counteracts IL-21-induced apoptosis in an EBV-positive diffuse large B-cell lymphoma cell line.
23364893Here, as a first approach toward the characterization of the role of EBV in DLCBL, the EBV gene expression and the IL-21 sensitivity of the EBV-positive DLBCL line, Farage, have been examined.
23364893It was found that, surprisingly, despite c-Myc upregulation, IL-21 induced cell proliferation rather than apoptosis in Farage.
23364893Expression of a dominant-negative EBNA1 mutant and the consecutive downregulation of EBV gene expression antagonized the IL-21-induced proliferation of Farage and increased apoptosis.
23364893These findings reveal a previously unknown role of EBV in DLBCL that is of possible relevance for the current attempt to use IL-21 in therapy.
23384681CD40 ligand and IL-21 was abolished.
23384903OBJECTIVE: To explore the effects of humanized interleukin 21 (IL-21) on anti-leukemic activity of cytokine induced killer(CIK) cells derived from peripheral blood(PB) and the mechanism.
23384903Proliferation of CIK cells with or without IL-21 stimulation and their cytotoxic activity against K562 cells was measured by MTT method.
23384903IL-21 receptor (IL-21R) and immunophenotypes of CIK cells were measured by flow cytometry.
23384903RESULTS: After IL-21 stimulation, the proportion of CIK cells increased from (17.
23384903CONCLUSION: Humanized IL-21 could enhance the anti-leukemic activity of CIK cells via increasing IL-21R, perforin, granzyme B, FasL, IFN-γ and TNF-α, as well as activating JAK-STAT signaling pathway.
23384903These data indicate that IL-21 has a potential clinical value in the enhancement of anti-leukemic immunotherapy.
23384943IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain.
23384943Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase.
23384943Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5.
23384943Our findings show for the first time that IL-21 induces GrB(+) human Bregs.
23403044These cells differ from TH1, TH2, and TH17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13.
23403044OBJECTIVE: We sought to obtain in vitro a population close to the TFH cells and to study the presence of this cell population among patients with autosomal dominant hyper-IgE syndrome carrying heterozygous signal transducer and activator of transcription 3 (STAT3) mutations that impair the IL-21 signaling required for B-cell differentiation.
23403044The ability of STAT3-deficient TFH cells to produce IL-21 on CD28/T-cell receptor activation and to proliferate did not differ from that observed for control TFH cells in vitro.
23415570Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72.
23415570This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43.
23415570However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable.
23415570This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons.
23415570Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease.
23415570By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.
23425147Using NTx-PD-1(-/-) mice, we found that in AIG lesions, interferon-γ, and tumor necrosis factor (TNF)-α together with interleukin-21 (IL-21) were highly expressed in the inflamed gastric mucosa.
23425147In addition, as with the injection of dexamethasone, in vivo administration of either anti-TNF-α or anti-IL-21 suppressed the development of AIG in NTx-PD-1(-/-) mice.
23425147CONCLUSIONS: These data reveal the essential role of IL-21 in the development of AIG and suggest that in addition to corticosteroids, anti-TNF-α as well as anti-IL-21 have the potential to induce the remission of AIG, offering additional therapeutic options for AIG patients.
23440042Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.
23440042The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5.
23440042We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity.
23447018The last four treated patients received CTL clones generated with exposure to interleukin-21 (IL-21) to prolong in vivo CTL survival, because IL-21 can limit terminal differentiation of antigen-specific T cells generated in vitro.
23447018CTLs generated in the presence of IL-21, which were transferred in these latter three patients and the patient with MRD, all remained detectable long-term and maintained or acquired in vivo phenotypic and functional characteristics associated with long-lived memory CD8 T cells.
23448944BACKGROUND: IL22RA1 (Interleukin 22 receptor-alpha 1), a member of the class II cytokine receptor family, mediates diverse biologic activities and appears to be important in pathogen defense, wound healing, and tissue reorganization.
23448944One promoter SNP of IL22, -429C/T (rs2227485), and one SNP of IL22RA1, Arg518Gly (rs3795299) were analyzed using direct sequencing.
23467775Interleukin-21 (IL-21) is a cytokine whose actions are closely related to B cell differentiation into plasma cells as well as to CD8(+) cytolytic T cell effector and memory generation, influencing the T lymphocyte response to different viruses.
23467775We observed in a pediatric patient with XLP-1 that IL-21 was expressed in nearly all peripheral blood CD4(+) and CD8(+) T cells.
23467775However, IL-21 could not be found in the lymph nodes, suggesting massive mobilization of activated cells toward the infection's target organs, where IL-21-producing cells were detected, resulting in large areas of tissue damage.
23468834We also assessed functionality of the T cells by evaluating the secretion of several inflammatory cytokines (IL-17A, IFN-gamma, IL-2, IL-33, TNF-alpha, IL-21, IL-22, and IL-27), from cell-sorted purified CD4+ and CD8+ T cells isolated from lesional and unaffected skin biopsies of psoriasis patients.
23468834Sorted CD4+ T cells from psoriatic lesional skin produced higher levels of IL-17A, IL-22, and IFN-gamma compared to unaffected skin, while sorted CD8+ T cells from lesional skin produced higher levels of IL-17, IL-22, IFN-gamma, TNF-alpha, and IL-2 compared to unaffected skin.
23474188Efficient production of recombinant IL-21 proteins for pre-clinical studies by a two-step dilution refolding method.
23474188Produced by CD4(+) helper T cells and natural killer T (NKT) cells, interleukin-21 (IL-21) performs broad regulatory functions on B cells, CD4(+) T cells, CD8(+) T cells, NK cells and NKT cells.
23474188Targeting IL-21 to enhance the immune system has attracted great interests in the development of vaccination, anti-infection and anti-tumor therapies.
23474188Administration of IL-21 in pre-clinical models is however limited by relatively high expense of the recombinant IL-21 protein.
23474188The method has been validated to produce milligrams of human IL-21, human IL-21/IL-4 chimera and mouse IL-21 with high bioactivities and low endotoxin, mostly suitable for in vitro and in vivo pre-clinical studies.
23474849TAR DNA binding protein and fused in sarcoma (FUS) are both RNA processing proteins whose dysfunction impacts on global cellular RNA regulation.
23474849The recent discovery that expression of repeat expansions in the C9orf72 gene may induce RNA foci that could sequester RNA binding proteins such as TAR DNA binding protein and FUS highlights a further possibly important mechanism of RNA dysfunction in disease.
23474849Furthermore, sequestration of key RNA binding proteins may also play an important role in sporadic disease due to the association of TAR DNA binding protein and FUS with stress granules.
23474849Notably these two key pathways interact; TAR DNA binding protein and FUS bind and regulate key aggrephagy-related genes whereas dysfunction of aggrephagy leads to cytoplasmic relocalization and aggregation of TAR DNA binding protein.
23475201In fact, we show that engagement of PD-1 on TFH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion.
23475201We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro.
23486778Up to 60% of these ICOS+CXCR3+CXCR5+CD4+ T cells were specific for influenza antigens and expressed interleukin-2 (IL-2), IL-10, IL-21, and interferon-γ upon antigen stimulation.
23493630Interleukin-6 receptor blockade selectively reduces IL-21 production by CD4 T cells and IgG4 autoantibodies in rheumatoid arthritis.
23493630However, tocilizumab treatment causes a selective decrease of IL-21 production by memory/activated CD4 T cells.
23493630Since IL-21 is known to promote plasma cell differentiation, we examined the effect of tocilizumab on the production of autoantibodies.
23493630In addition, we show that IL-21 is a powerful inducer of IgG4 production by B cells.
23493630Thus, IL-6 contributes to the presence of IgG4-specific anti-CCP autoantibodies in RA patients, likely through its effect on IL-21 production by CD4 T cells, and IL-6R blockade down-regulates this pathway.
23505568Stimulation of primary human B cell and peripheral blood mononuclear cell (BT) co-cultures with α-IgM and a non-mitogenic concentration of superantigens for three days promoted a Th17 cell response as evidenced by increased expression of Th17-related gene transcripts, including Il17f, Il21, Il22, and Il23r, in CD4 T cells, as well as the secretion of IL-17A and IL-17F protein.
23507192Sera of 64 ANA-positive patients (12 homogeneous, 13 speckled particle, 11 nucleolar, 15 centromere, 6 peripheral nuclear) and 16 healthy donors were analyzed for IL-17, IL-6, IL-21, IL-22, IL-23 (p19), and TGF-β, and subsequently correlations between IL-17 and IL-6, IL-21, IL-22, IL-23, and TGF-β were analyzed.
23507192Among them, IL-21 and IL-22 were higher with all ANA-positive sera and IL-17, IL-6, and IL-23 were higher with three or more ANA staining sera.
23508371Production of IL-17 and IL-21 was inhibited by the addition of a ROCK inhibitor.
23515130In particular, JAK3 is the only JAK family member that associates with just one cytokine receptor, the common gamma chain, which is exclusively used by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 critically involved in T and natural killer (NK)-cell development, and B-cell function and proliferation.
23553807Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, regulates multiple innate and adaptive immune responses.
23553807Indeed, IL-21 controls the proliferation and function of CD4+ and CD8+ T lymphocytes, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, enhances the activity of natural killer cells and negatively regulates the differentiation and activity of regulatory T cells.
23553807Moroever, IL-21 can stimulate nonimmune cells to synthesize various inflammatory molecules.
23553807Excessive production of IL-21 has been described in many human chronic inflammatory disorders and there is evidence that blockade of IL-21 helps attenuate detrimental responses in mouse models of immune-mediated diseases.
23553807In this article we briefly review data supporting the pathogenic role of IL-21 in immune-inflammatory pathologies and discuss the benefits and risks of IL-21 neutralization in patients with such diseases.
23557800Interleukin-21 (IL-21) is overproduced in human intestines affected by inflammatory bowel disease (IBD) and in the gut of mice with DSS-induced colitis.
23557800We previously identified a novel IL-21 isoform named IL-21iso.
23557800In this study, we found that in addition to the conventional IL-21, IL-21iso mRNA was also expressed in the colon with DSS-induced colitis.
23557800These results indicate that besides IL-21, IL-21iso may be another regulator of gut inflammation.
23566938RNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients.
23566938Significantly enhanced IL-21 protein levels were noted in both CC and LC patients.
23566938Increased mucosal mRNA levels of IFN-γ, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients.
23571506It is unclear whether interleukin (IL)-21 and IL-17A contribute to CD onset and lesion severity; therefore, we investigated IL-21 and IL-17A expression in biopsies from pediatric CD patients with different histopathological scores.
23571506High numbers of IL-21-producing cells were observed in pediatric CD lesions, even Marsh 1-2 lesions, whereas increased numbers of IL-17 secreting cells were not observed.
23571506Intraepithelial lymphocytes, CD4(+) T cells and also neutrophils secreted IL-21.
23571506Adult CD patient biopsies also contained high numbers of IL-21-positive cells; however, enhanced numbers of IL-17-positive cells were observed in a small subgroup of patients with severe lesions.
23578511IL-21 lentiviral vector was constructed and used to transfect 293T cells.
23578511Immunophenotypes of CIK cells, IL-21 receptor (IL-21R) and FasL on the surface of CIK cells, intra-cellular perforin and granzyme B of CIK cells were measured by flow cytometry.
23578511RESULTS: By restriction enzyme digestion and sequencing, IL-21 lentiviral vector was identified, after transfecting virus supernatant into CIK cells, the expression of IL-21 was detected in CIK cells.
23578511It was stronger and longer compared to the exogenous effect of IL-21 (from 22.
23578511Thus IL-21 may potentially enhance the anti-leukemic immunotherapy.
23607532Expression of IL-21, IL-17A and retinoic acid-related orphan receptor C (RORC) in intestinal mucosa were analysed by quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry.
23607532IL-21 and Th17 cells were found to be expressed highly in inflamed mucosa of active CD patients compared with healthy controls.
23607532Ten weeks after IFX infusion, CD activity index, ESR, CRP and intestinal mucosal healing were improved markedly in CD patients, and IL-21 expression and Th17 cell infiltration were decreased significantly compared with those before IFX therapy.
23607532In-vitro study demonstrated that IFX treatment could suppress IL-21, IL-17A and RORC expression in cultured CD biopsies.
23607532Moreover, IFX was also observed to down-regulate markedly IL-17A, IL-21 and RORC expression by CD CD4(+) T cells.
23607532IFX is highly effective in inducing clinical remission and promoting intestinal mucosal healing in CD patients through down-regulation of IL-21 expression and Th17 cell infiltration in intestinal mucosa.
23607664We have shown recently that IL-21 may promote activation of autoreactive CD8(+) T cells by increasing their antigen responsiveness.
23607664To investigate the role of IL-21 in activating diabetogenic CD8(+) T cells in the NOD mouse, we generated IL-21-deficient NOD mice expressing the highly pathogenic major histocompatibility complex (MHC) class-I-restricted 8.
23607664IL-21 deficiency protected 8.
23607664IL-21-deficient 8.
23607664IL-21-deficient environment showed impaired antigen-specific proliferation in vivo even in IL-21-sufficient mice.
23607664These findings indicate that IL-21 is required for efficient initial activation of autoreactive CD8(+) T cells but is dispensable for the activated cells to develop effector functions and cause disease.
23607664Hence, therapeutic targeting of IL-21 in T1D may inhibit activation of naive autoreactive CD8(+) T cells, but may have to be combined with other strategies to inhibit already activated cells.
23610619Specifically, findings regarding JAK3, SHP1 and the stimulatory effects of several cytokines including interleukin (IL)-9, IL-21 and IL-22 are summarized.
23622563The levels of IL-21, IL-23, and TGF-β1 were positively correlated (IL-23/IL-21, r = 0.
23622563TGF-β1/IL-21, r = 0.
23622563Our results suggest that IL-21, IL-23, and TGF-β1 may play an important role in the development of site-specific Th17 cell-mediated inflammation in BSRC, which underscore the importance of systemic therapy and offer new insights into the potential of targeted treatments.
23637417In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections.
23637417Using IL-21 receptor-deficient (IL-21R(-/-)) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (TFH)-like cells in the absence of IL-21 signaling.
23637417Using chimeric mice containing wild-type or IL-21R(-/-) CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity.
23637417Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses.
23638156IL-21 in Lupus-prone MRL/lpr mice.
23638156Here, we investigated the percentages of Tfh cells and B10 cells in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the effects and mechanism of Tfh cell-derived interleukin-21 (IL-21) on IL-10 production during the differentiation of B10 cells.
23638156Tfh cell-derived IL-21 from MRL/lpr mice could promote IL-10 production during the differentiation of B10 cells.
23638156Importantly, neutralization of IL-21 inhibited IL-10 production and expansion of B10 cells both in vitro and in vivo.
23638156Moreover, IL-21-induced IL-10 exerted a regulatory function by inhibiting the proliferation of T cells.
23638938LC-MS/MS assay for quantification of human and cynomolgus monkey interleukin 21 (IL-21) was developed, qualified, and implemented.
23638938IL-21 was not detected in serum from normal healthy volunteers or from autoimmune disease patients.
23638938However, IL-21 levels were quantified in cynomolgus monkey spleen and colon tissue and normal and inflammatory bowel disease (IBD) human colon tissue as well as hyperplasia human tonsils.
23653308The collective data have shown that transforming growth factor-β (TGF-β), interleukin (IL)-6, IL-1β, IL-21, and IL-23 are involved in the differentiation program of Th17 cells.
23653308Among the Th17-related effector cytokines, such as IL-17, IL-17F, IL-21, and IL-22, IL-17 is regarded as a key cytokine to induce inflammatory responses.
23656167Association of IL-17, IL-21, and IL-23R gene polymorphisms with HBV infection in kidney transplant patients.
23656167In this study, the association between IL-17, IL-23R, and IL-21 gene polymorphisms with hepatitis B virus (HBV) infection was evaluated in kidney transplant patients.
23656167The cytokine gene polymorphisms, including IL-17 197 A/G (rs2275913), IL-21 +1472 G/T (rs2055979), IL-21 5250 C/T (rs4833837), and IL-23R C/A (rs10889677) were evaluated by PCR-RFLP and ARMS-PCR protocols.
23656167The serum levels of IL-17 and IL-21 were analyzed in HBV infected and noninfected transplant patients by ELISA methods according to manufacturer's instructions.
23656167IL-23R (rs10889677) polymorphism, a higher frequency of AG heterozygote genotype and A allele of IL-17-G197A (rs2275913) polymorphism, a higher frequency of TT homozygote genotype and T allele of IL-21-G1472T (rs2055979) polymorphism, and a higher frequency of CC homozygote genotype and C allele of IL-21-C5250T (rs4833837) polymorphism were found in HBV-infected kidney transplant patients with acute rejection.
23656167Diagnosis of the higher frequency of the IL-17, IL-21, and IL-23R cytokine genotypes and allele polymorphisms in HBV-infected kidney transplant patients who experienced acute rejection, illustrates the importance of Th17-related cytokine genetic patterns.
23686809OBJECTIVE: To see whether the distribution patterns of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.
23686809METHODS: pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.
23686809INTERPRETATION: pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways.
23688998OBJECTIVE: To investigate the effects of dexamethasone on the expression of interleukin-21 (IL-21) and phospho- STAT3 (p-STAT3) in a murine model of chronic asthma.
23688998The airway inflammation was evaluated by HE staining, and the expressions of IL-21 and p-STAT3 in the lung tissue were detected by immunohistochemistry and Western blotting.
23688998Compared with the control group, the asthmatic group showed significantly increased protein expressions of IL-21 and p-STAT3 (P<0.
23688998CONCLUSION: Dexamethasone can inhibit the expression of IL-21 and p-STAT3 in the murine model of chronic asthma, suggesting the importance of IL-21/STAT3 signaling pathway in the therapeutic mechanisms of dexamethasone for asthma.
23696826An overexpression of the genes encoding IL-17a, IL-17F, IL-21, IL-22 and INF-γ was found in milk cell RNA extracts in the early phase of the inflammatory response.
23696826In mammary tissue from challenged quarters, overexpression of the genes encoding IL-17A, IL-17F, IL-21, IL-22, IL-26 and IFN-γ was observed.
23703545Circulating chemokine (C-X-C Motif) receptor 5(+) CD4(+) T cells benefit hepatitis B e antigen seroconversion through IL-21 in patients with chronic hepatitis B virus infection.
23703545These cells were able to produce a significantly higher level of intracellular interleukin 21 (IL-21) after stimulation with HBV peptides in patients with telbivudine-induced HBeAg seroconversion (P = 0.
23703545Of note, the increase in frequency of anti-HBe-secreting B cells was abrogated by soluble recombinant IL-21 receptor-Fc chimera (P = 0.
23703545IL-21 enhanced this effect (P = 0.
23703545CONCLUSION: Circulating CXCR5(+) CD4(+) T cells, by producing IL-21, may have a significant role in facilitating HBeAg seroconversion in patients with chronic HBV infection.
23719242Similarly, a recently developed NK cell expansion system employing IL-2 plus lethally irradiated K562 feeder cells constitutively expressing membrane-bound IL-21 (K562 clone 9.
23738704The addition of IL-21 down-modulated the protective effect of all the stimuli on CD27(-) B cells and the protective effect of CpG-ODN and anti-IgM on CD27(+) B cells.
23738704In contrast, IL-21 rescued unstimulated CD27(-) B cells and improved the rescue of anti-CD40-stimulated CD27(+) B cells.
23738704When we compared patients and controls, mainly CD27(+) B cells from MB0 patients were less sensitive to rescue from apoptosis than those from MB1 patients and controls after activation, irrespective of the IL-21 effect.
23782146TNF-α, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-γ ), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN-β-1a), 3.
23786438In comparison with HC, significantly higher percentages of circulating IgD⁺ CD27⁻ CD19⁺ naive B, CD86⁺ CD19⁺ and CD95⁺ CD19⁺ activated B, CD3⁺ CD4⁺ CXCR5⁺, CD3⁺ CD4⁺ CXCR5⁺ ICOS⁺, CD3⁺ CD4⁺ CXCR5⁺ PD-1⁺ and CD3⁺ CD4⁺ CXCR5⁺ ICOS⁺ PD-1⁺ Tfh cells but lower IgD⁺ CD27⁺ CD19⁺ preswitch memory B cells were detected, accompanied by significantly higher levels of serum IL-21 in the RA patients.
23792271The results showed that the expressions of IL-6, IL-1β, IL-17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients.
23825648In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma.
23825945Microarray analysis of TCR (anti-CD3/CD28) stimulated DN T cells indicated that these cells are multifunctional and upregulate genes with marked similarity to CD4 T cells, such as immune genes associated with Th1 (IFNγ), Th2 (IL4, IL5, IL13, CD40L), Th17 (IL17, IL22) and TFH (IL21, ICOS, IL6) function, chemokines such as CXCL9 and CXCL10 and transcription factors known to be actively regulated in CD4 T cells.
23826263An HIV-1 envelope glycoprotein trimer with an embedded IL-21 domain activates human B cells.
23826263The immunogenicity of Env can be increased by fusion to co-stimulatory molecules and here we describe novel soluble Env trimers with embedded interleukin-4 (IL-4) or interleukin-21 (IL-21) domains, designed to activate B cells that recognize Env.
23826263In particular, the chimeric Env(IL-21) molecule activated B cells efficiently and induced the differentiation of antibody secreting plasmablast-like cells.
23826263We studied whether we could increase the activity of the embedded IL-21 by designing a chimeric IL-21/IL-4 (ChimIL-21/4) molecule and by introducing amino acid substitutions in the receptor binding domain of IL-21 that were predicted to enhance its binding.
23826263In addition, we incorporated IL-21 into a cleavable Env trimer and found that insertion of IL-21 did not impair Env cleavage, while Env cleavage did not impair IL-21 activity.
23826263These studies should guide the further design of chimeric proteins and Env(IL-21) may prove useful in improving antibody responses against HIV-1.
23828737Since its discovery in 2000, IL-21 has been shown to play critical roles in the regulation of both innate and adaptive immune responses.
23828737IL-21 is produced predominantly by multiple effector CD4+ T-cell types [T helper 17 (Th17), follicular helper T (TFH), and other activated CD4+ cells] and NKT cells.
23828737In addition to T cell receptor (TCR) signals, the production of IL-21 by activated CD4+ T cells is intricately regulated by various extrinsic factors and intrinsic molecules, such as IL-6, IL-21, ICOS, Stat3, IRF4, and Batf.
23828737Because IL-21 receptor (IL-21R) is broadly expressed on T, B, NK, and dentritic cells (DCs), IL-21 signaling via Jak-Stat and other pathways has direct pleiotropic effects on their proliferation, differentiation, and effector function.
23828737For instance, while Th17 and TFH cells produce IL-21, IL-21 also facilitates the development of these cells.
23828737IL-21-producing TFH cells are important for the generation and maintenance of germinal centers, and control the differentiation of germinal center B cells and immunoglobulin production.
23828737IL-21 also enhances expansion and cytotoxicity of CD8+ effector T cells.
23828737During chronic lymphocytic choriomeningitis viral infection, chronic IL-21 production by antigen-specific CD4+ T cells is needed to sustain CD8+ T cell function for viral control.
23828737IL-21 is also required for the development of T cell-mediated type 1 diabetes in NOD mice, possibly through sustaining effector T cell function in a similar manner.
23828737IL-21 as well as the therapeutic potential of targeting IL-21 in transplantation.
23830147IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease.
23830147However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown.
23830147OBJECTIVE: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade.
23830147Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro.
23830147Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells.
23836781Characterization of human sporadic ALS biomarkers in the familial ALS transgenic mSOD1(G93A) mouse model.
23836781Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of motor neurons.
23836781Although most cases of ALS are sporadic (sALS) and of unknown etiology, there are also inherited familial ALS (fALS) cases that share a phenotype similar to sALS pathological and clinical phenotype.
23836781Together with the previously discovered ones-CyFIP2 and RbBP9, we investigated whether these four potential ALS biomarkers may be differentially expressed in tissues obtained from mutant SOD1(G93A) transgenic mice, a model that is relevant for at least 20% of the fALS cases.
23853592We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections.
23853592IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation.
23853592Compared to untreated animals, IL-21-treated RMs showed (i) higher expression of perforin and granzyme B in total and SIV-specific CD8⁺ T cells and (ii) higher levels of intestinal Th17 cells.
23853592In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells.
23853592Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy.
23877403Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100 ± 28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥ 0.
23889847Polymorphisms of interleukin-21 and interleukin-21-receptor genes confer risk for autoimmune thyroid diseases.
23889847In this study, we investigated whether polymorphisms of the IL-21 and IL-21R are associated with Graves' disease (GD) and Hashimoto's thyroiditis (HT), two major forms of AITDs, among a Chinese population.
23889847METHODS: Rs907715, rs4833837, rs2221903 and rs2055979 of the IL-21 gene and rs3093301 and rs2285452 of the IL-21R gene were explored in a case-control study including 405 GD, 228 HT patients and 242 controls.
23889847RESULTS: For IL-21 gene, we identified and confirmed a higher prevalence of A alleles of rs2221903 (P = 0.
23894713IL-21 in cancer immunotherapy: At the right place at the right time.
23894713Interleukin-21 (IL-21) has been described as a potent stimulator of antitumor T-cell immunity, but also of autoimmune reactions and oncogenesis.
23894713Antigen presenting cells genetically modified to release IL-21 allow for the expansion of tumor-specific T cells exhibiting favorable effector and growth characteristics and a minimal risk of detrimental side effects.
23905760AIM: Interleukin-21 (IL-21) is involved in effective primary hepatic immune response against hepatitis B virus (HBV) and profibrotic function.
23905760However, the role of IL-21 in HBV-associated liver cirrhosis is poorly understood.
23905760This study aimed to investigate the role of IL-21 in HBV-associated liver cirrhosis and possible mechanisms.
23905760The frequencies of IL-21(+) CD4(+) T cells were detected by flow cytometry, and the level of IL-21 in plasma was measured by enzyme-linked immunoassay.
23905760The distribution of IL-21(+) cells in situ in liver was observed by immunohistochemistry.
23905760RESULTS: Increased peripheral number of IL-21(+) CD4(+) cells, elevated plasma level of IL-21 and IL-21(+) cell accumulation in liver were observed in patients with HBV-associated liver cirrhosis.
23905760In vitro administration of IL-21 was accompanied with increased expression of α-SMA, inhibited LX-2 cells apoptosis and upregulated collagen production by LX-2 cells.
23905760CONCLUSION: IL-21 may contribute to the fibrogenesis of HBV-associated liver cirrhosis by activating the hepatic stellate cells.
23905760Therefore, neutralization of IL-21 could be a favorable new therapeutic strategy for liver cirrhosis treatment.
23940329Human circulating influenza-CD4+ ICOS1+IL-21+ T cells expand after vaccination, exert helper function, and predict antibody responses.
23940329In lymph nodes and tonsils, T-follicular helper cells have been identified as the T cells subset specialized in helping B lymphocytes, with interleukin-21 (IL-21) and inducible costimulatory molecule (ICOS1) playing a central role for this function.
23940329We followed the expansion of antigen-specific IL-21(+) CD4(+) T cells upon influenza vaccination in adults.
23940329We show that, after an overnight in vitro stimulation, influenza-specific IL-21(+) CD4(+) T cells can be measured in human blood, accumulate in the CXCR5(-)ICOS1(+) population, and increase in frequency after vaccination.
23940329The expansion of influenza-specific ICOS1(+)IL-21(+) CD4(+) T cells associates with and predicts the rise of functionally active antibodies to avian H5N1.
23940329We also show that blood-derived CXCR5(-)ICOS1(+) CD4(+) T cells exert helper function in vitro and support the differentiation of influenza specific B cells in an ICOS1- and IL-21-dependent manner.
23940329We propose that the expansion of antigen-specific ICOS1(+)IL-21(+) CD4(+) T cells in blood is an early marker of vaccine immunogenicity and an important immune parameter for the evaluation of novel vaccination strategies.
23953581We assessed the percentages of CD4(+)CXCR5(+) follicular T helper cells, CD4(+)FoxP3(+) regulatory T cells (Treg) and expressions of IL-17, IL-21, FoxP3, Bcl-6 in the spleen.
23953581Combined treatment increased the percentage of Treg and the expression of Foxp3 and IL-21, meanwhile inhibiting the expression of Bcl-6.
23954997Thirty cytokines, including IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-17C, IL-21, IL-22, IL-23p19, IL-28A, IL-29, CCL5, CCL16, CCL20, CCL22, CXCL9, CXCL10, CXCL11, TNFRSF8, TNFRSF18, IL-6R, gp130, and TGF-β1, were measured using a human cytokine antibody array.
23954997RESULTS: Significant differences of signal intensities were observed for IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-21, IL-23p19, IL-28A, and IL-29.
23954997Among three HBV infection groups, significant differences were observed in IL-2, IL-4, IL-12p70, IL-15, IL-21, IL-23p19, and IL-29.
23956763Th17) cells are characterized by producing interleukin-17 (IL-17, also called IL-17A), IL-17F, IL-21, and IL-22 and potentially TNF- α and IL-6 upon certain stimulation.
23960240The cellular source and target of IL-21 in K/BxN autoimmune arthritis.
23960240IL-21 is a pluripotent cytokine that regulates B cell and plasma cell differentiation and is thought be an autocrine factor for follicular helper T cell (T(FH)) and Th17 differentiation.
23960240Although IL-21 has been implicated in autoimmune diseases, its relevant cellular source and target cells have not been well characterized.
23960240By comparing transfer of T or B cells deficient in IL-21 or IL-21R, we were able to dissect the contribution of each cell type.
23960240IL-21 did not induce GC formation or autoantibody production, but they went through normal T(FH) differentiation.
23960240However, T cells lacking IL-21R induced Ab titers, GC B cell frequency, and arthritis development similar to wild-type T cells, suggesting that IL-21 is not required for T(FH) differentiation and function.
23960240IL-21 acts on B cells, because IL-21R expression on B cells was required to induce disease.
23960240In contrast, Th17 cells, a T cell subset that also produces IL-21 and can provide help to B cells, are not required for the GC response and arthritis.
23980207They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-γ that inhibited Foxp3 expression.
23992866IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis.
23992866IL-21 receptor deficiency did not affect peripheral T cell activation or trafficking, but dampened granzyme B, gamma interferon and IL-10 expression by CNS T cells and reduced serum and intrathecal humoral responses.
23992866These data demonstrate a critical role of IL-21 in regulating CNS immunity, sustaining viral persistence and preventing mortality.
23993651Here we showed that T cell-specific ablation of the common interleukin-6 (IL-6) family receptor, gp130, profoundly compromised virus-specific CD4⁺ T cell survival, T follicular helper responses, and IL-21 production at late stages of chronic lymphocytic choriomeningitis virus (LCMV) infection.
23993651We identified IL-27 as a gp130 cytokine that promoted antiviral CD4⁺ T cell accumulation in vivo and that rapidly induced IL-21 ex vivo.
23994109In this study, we show that initial Th1 and in particular Th2 polarization was negatively influenced by even small percentages (<5-10%) of "polluting" memory CD4+ T cells producing IL-5, IL-9, IL-10 IL-13, IL-21, IL-22, IL-31 and IFN-γ that are normally found after standard immunomagnetic bead separation of naïve CD4+ T cell.
23998605According to supplement of different stimulatory factors (CD28 mAb, IL-15 and IL-21), the experiment was divided into five groups:control group (CIK), CB28+IL-15+IL-21 group, IL-15+IL-21 group, CD28+IL-15 group and CD28+IL-21 group.
23998605The highest proliferation index on days 10 was observed in group CD28mAb, IL-15 and IL-21(255.
23998605IL-21+IL-15 group and CD28 mAb+IL-21 group (166.
23998605The highest IFN-γsecretion was found in CD28 mAb, IL-15 and IL-21 groups.
24022125RESULTS: In CD4+ T cells from chronically challenged mice, expression of mRNA for Th17 cytokines IL-17A, IL-17F, IL-21 and IL-22 was significantly increased.
24023776We recently reported that interleukin-21 (IL-21) has a unique ability to expand the small subset of DP thymocytes (CD69(+)) which are ongoing positive selection, and that administration of IL-21 increases thymic output in aged mice.
24023776The goal of this study was to evaluate whether IL-21 could mitigate GC-induced thymic atrophy.
24023776Accordingly, CD69(-) DP thymocytes from PBS-treated mice were unresponsive to IL-21 administration.
24023776However, following GC injection, surviving CD69(-) DP thymocytes up-regulated IL-21R and responded to IL-21 treatment as evidenced by enhancement of Bcl6 expression and phosphorylation of STAT1, STAT3 and STAT5.
24023776Consequently, IL-21 administration to GC-treated mice accelerated thymic recovery by expanding considerably DP thymocytes and, to a lesser extent, DN thymocytes.
24023776However, IL-21-induced expansion of DN/DP thymocytes did not alter the diversity of the intrathymic or peripheral T-cell receptor (TCR) repertoire.
24023776We conclude that IL-21 dramatically accelerates recovery from GC-induced thymic atrophy.
24052636Ocular surface IFN-γ, IL-6, and IL-21 were significantly decreased by topical HL036.
24052636CONCLUSIONS: Topical TNF-α blockers effectively suppressed lacrimal gland and corneal inflammation by suppressing IFN-γ, IL-21, and IL-6.
24062161Emerging lines of evidence suggest a relationship between amyotrophic lateral sclerosis (ALS) and protein sumoylation.
24062161Multiple studies have demonstrated that several of the proteins involved in the pathogenesis of ALS, including superoxide dismutase 1, fused in liposarcoma, and TAR DNA-binding protein 43 (TDP-43), are substrates for sumoylation.
24062161Additionally, recent studies in cellular and animal models of ALS revealed that sumoylation of these proteins impact their localization, longevity, and how they functionally perform in disease, providing novel areas for mechanistic investigations and therapeutics.
24062161In this article, we summarize the current literature examining the impact of sumoylation of critical proteins involved in ALS and discuss the potential impact for the pathogenesis of the disease.
24080172In addition to the dysplastic gangliocytoma, the patient showed typical transactive response DNA-binding protein with Mr 43 kD (TDP-43) pathology mainly in the cortex and the substantia nigra and numerous p62-positive/TDP-43-negative inclusions in the cerebellar granule cells.
24080172Our findings confirm that the clinical and pathologic picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrants further studies on the possible involvement of phosphatase and tensin homolog gene pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.
24101550This study analyzes the effect of IL-10, IL-21, and IL-6 on human in vivo-generated PCs isolated from secondary lymphoid organs, blood (circulating, recently Ag-induced PCs), and bone marrow.
24101550However, IL-10, IL-21, and IL-6 commonly induce STAT-3 phosphorylation in the three PC subsets, and all of their effects are exerted strictly through the STAT-3 activation.
24114594This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner.
24114594Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins.
24120466The role of glia as a contributing factor to motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) is becoming increasingly appreciated.
24120466However, most studies implicating astrocytes have focused solely on models of ALS caused by superoxide dismutase 1 (SOD1) mutations.
24120466Since it is currently unknown how TDP-43 mutations cause disease, we derived astrocytes for study from both gain and loss of function mouse models of TDP-43.
24120466Astrocytes overexpressing mutant TDP-43(A315T) as well as astrocytes lacking TDP-43 were morphologically indistinguishable from wild-type astrocytes in vitro.
24120466These data indicate that astrocytes do not adopt the same toxic phenotype as mutant SOD1 astrocytes when TDP-43 is mutated or expression levels are modified.
24120466Our study reinforces the heterogeneity in ALS disease mechanisms and highlights the potential for future screening subsets of ALS patients prior to treatment with cell type-directed therapies.
24122347The results showed that IL-18BP significantly suppressed the expression of IL-17 as well as other proinflammatory genes such as transforming growth factor-β, prostaglandin E2 synthase, cyclooxygenase-2 in IL-1α-stimulated NC cells, and IL-18BP also significantly suppressed the expression of IL-17, IL-17R, IL-21 and IL-17-related transcriptional factor retinoic acid-related orphan nuclear receptor, signal transducer and activator of transcription-3 and Foxp3 in IL-1α-stimulated splenocytes cultured from EAM rats.
24126614PURPOSE OF REVIEW: The purpose of this study is to describe recent advances in our understanding of the role of interleukin-21 (IL-21) in B-cell maturation, and how defects in IL-21 receptor (IL-21R) signalling pathways (IL-21R/γc/JAK3/STAT3) are related to primary immune deficiencies.
24126614Common variable immunodeficiency is associated with impaired in-vitro development of peripheral blood mononuclear cells or purified B-cells into memory or CD38 B-cells following addition of IL-21.
24126614SUMMARY: IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting cells.
24126614IL-21 related defects may also be associated with reduced natural killer (NK)-cell cytotoxicity and TH17 cytokine production, indicating that abnormalities in the IL-21-IL-21R pathway have profound effects on crucial immune responses.
24159173IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts.
24159173We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations.
24159173IL-21 strongly induced CD25 (IL-2Rα) in normal, but not STAT3-deficient, CD40L-stimulated naïve B cells.
24159173IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process.
24159173IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naïve B cells stimulated with CD40L/IL-21.
24159173IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells.
24159173Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2.
24159173Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation.
24159173Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21.
24166135In psoriasis-like skin lesions elicited in mice by IL-21, topical application of GED-0507-34L reduced cellular infiltrate and epidermal hyperplasia, normalizing the differentiation process.
24170093Interleukin-21 (IL-21)+CD4+ T cells are involved in the immune response against hepatitis B virus (HBV) by secreting IL-21.
24170093However, the role of IL-21+CD4+ T cells in the immune response against chronic hepatitis C (CHC) virus infection is poorly understood.
24170093This study aimed to investigate the role of IL-21+CD4+ T cells in CHC patients and the potential mechanisms.
24170093The peripheral frequency of HCV-specific IL-21+CD4+ T cells was higher in the low viral load group and was negatively correlated with the serum HCV RNA viral load in all CHC patients.
24170093Meanwhile, IL-21+ cells accumulated in the liver in the low viral load group.
24170093In vitro, IL-21 treatment increased the expression of proliferation markers and cytolytic molecules on HCV-specific CD8+ T cells.
24170093In summary, these findings suggest that HCV-specific IL-21+CD4+ T cells might contribute to HCV control by rescuing HCV-specific CD8+ T cells in CHC patients.
24170860Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration.
24170860RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls.
24170860Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations.
24198283IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment.
24242760The effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor.
24242760IL-21 is secreted by activated CD4 T cells and natural killer T cells.
24242760Our research focus has been on the role of IL-21 and more recently of Tfh in immunopathogenesis of HIV infection.
24242760This review focuses on first the influence of IL-21 in regulation of T cell, B cell, and NK cell responses and its immunotherapeutic potential in viral infections and as a vaccine adjuvant.
24269703DESIGN AND METHODS: The levels of cytokines in bone marrow plasma including Th1-associated cytokine (IFN-γ), Th2-associated cytokine (IL-4), Th17-associated cytokines (IL-17, IL-6, TGF-β, and IL-21), regulatory T cell (Treg)-associated cytokines (IL-35 and IL-10) and Th22-associated cytokine (IL-22) were examined by enzyme-linked immunosorbent assay (ELISA) in AML patients and controls.
24269703RESULTS: Significant differences on cytokine levels tested were observed among the AML newly-diagnosed (ND) patients, AML patients in complete remission (CR) and controls except IL-21 and IL-35.
24269703In AML-ND group IFN-γ level was positively correlated with IL-21 or IL-22 level.
24269703Additionally, significant associations were observed between IL-17, IL-21 and some clinical characteristics.
24287789This study aimed to investigate the serum levels of IL-21 in GD patients and to explore their association with disease activity.
24287789Changes in serum IL-21 were also observed in 12 GD patients before and after treatment.
24287789Additionally, correlations among the serum IL-21 and free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), thyrotropin receptor antibody (TRAb), and TSAb were also analyzed.
24287789The serum IL-21 levels in all GD patients were significantly higher than those in the control group (P < 0.
24287789GD-untreated and GD-recurrence groups had elevated serum IL-21 compared to the control group (P < 0.
24287789Moreover, serum IL-21 in newly diagnosed patients markedly decreased after treatment (P < 0.
24287789Additionally, the serum IL-21 levels in GD-goiter patients were higher than those of the GD-non-goiter patients (P < 0.
24287789However, no significant differences were found in the serum IL-21 levels in patients with or without Graves' ophthalmopathy.
24287789Importantly, serum IL-21 positively correlated with FT3, FT4, TPOAb, TGAb, and TRAb (r = 0.
24287789Serum IL-21 levels were significantly elevated in patients with GD and decreased after treatment; moreover, IL-21 may be associated with the clinical disease activity.
24289584Multiple cytotoxic factors involved in IL-21 enhanced antitumor function of CIK cells signaled through STAT-3 and STAT5b pathways.
24289584Dual properties of IL-21 in activating T cells and reducing activation induced cell death led us to explore the mechanism of action of IL-21 enhanced proliferation and cytotoxic potential of CIK cells.
24289584METHOD: CIK cells cultured from PBMCs of healthy subjects were stimulated with IL-21 and cellular viability and cytotoxicity to K562 cells were measured.
24289584RESULTS: We found that IL-21 did not enhance in vitro proliferation of CIK cells, but did increase the number of cells expressing the CD3+/ CD56+ phenotype.
24289584We further affirmed that IL-21 signals through the STAT-3 and STAT- 5b signaling pathway in the CIK cell pool.
24289584CONCLUSION: IL-21 enhances cytotoxic potential of CIK cells through increasing expression of perforin, granzyme B, IFN-gamma and TNF-alpha.
24323496The frequencies of IL-21-producing T cells and serum levels of IL-21 were determined by flow cytometry analysis and ELISA, respectively, in 24 ITP patients and nine healthy controls.
24323496RT-PCR showed that the frequencies of circulating IL-21-producing T cells and serum levels of IL-21 were significantly higher in ITP patients than that in healthy controls.
24325470Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels.
24326545IL-15 signals through a heterotrimeric receptor involving the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ) shared with IL-2 and a private IL-15Rα subunit.
24350772Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1.
24350772METHODS: A recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor (GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects determined in a mouse model of subcutaneous liver cancer.
24350772Activation of host immunity might have contributed to this effect by promoting increased numbers and cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and Rae-1.
24372156Expression of IL-17, but also IL-21 and IL-22, was observed in all eczema subtypes.
24376448Moreover, numerous other activating or inhibitory cytokines such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-18, IL-21, Transforming growth factor-β (TGFβ) and type I interferons regulate their activation and their effector functions at different stages of the immune response.
24389059Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete granzyme B (GrB), which plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance.
24416451CD8⁺ T cells cultured alone revealed that IL-21, another γc cytokine, was capable of rescuing their survival under IL-2 deprivation.
24416451Indeed, blocking the IL-21 signaling pathway along with IL-2 neutralization resulted in significantly reduced survival of both CD4⁺ and CD8⁺ T cells.
24416451Taken together, we have shown that under IL-2 deprivation conditions, IL-21 may act as the major survival factor promoting T cell immune responses.
24416451Thus, investigation of IL-2 targeted therapies may need to be revisited to consider blockade of the IL-21 signaling pathways as an adjunct to provide more effective control of T cell immune responses.
24430438IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity.
24430438We found IL-21 and IL-21R mRNA expression upregulated in adipose tissue of high-fat diet (HFD) wild-type (WT) mice and in stromal vascular fraction from human obese subjects in parallel to macrophage and inflammatory markers.
24430438In a context of diet-induced obesity, IL-21 KO mice, compared with WT animals, exhibited lower body weight, improved insulin sensitivity, and decreased adipose and hepatic inflammation.
24430438Our data suggest that IL-21 exerts negative regulation on IRF4 and Treg activity, developing and maintaining adipose tissue inflammation in the obesity state.
24430489BACKGROUND: Interferon stimulated chemokine CXCL-10, interleukin (IL)-12 (p70) and IL-21 have been associated with HBsAg and HBeAg loss following treatment of HBV monoinfection.
24430489CXCL-10, IL-12 and IL-21 (Luminex Bead Array, Life Technologies, Grand Island, NY, USA) were measured in plasma prior to initiation of HBV-active cART (baseline), at the time of seroconversion (T0) and at the closest time point before (T-1) and after (T+1) seroconversion.
24430489There was no difference between SC and NSC in the level of CXCL-10, IL-12 and IL-21 at any time point.
24433387IL-21 (p = 0.
24444073Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice.
24444073The present study was aimed to investigate effect of hUCMSCs as vehicles for a constant source of transgenic interleukin-21 (IL-21) on ovarian cancer in vivo.
24444073METHODS: The hUCMSCs were engineered to express IL-21 via lentiviral vector- designated 'hUCMSCs-LV-IL-21', and then were transplanted into SKOV3 ovarian cancer xenograft-bearing nude mice.
24444073The expressed IL-21 in the supernatant from hUCMSCs-LV-IL-21 obviously stimulated splenocyte's proliferation.
24444073The hUCMSCs-LV-IL-21 significantly reduced SKOV3 ovarian cancer burden in mice indicated by tumor sizes compared with control mice.
24444073The expressed IL-21 not only regulated the levels of IFN-γ and TNF-α in the mouse serum but also increased the expression of NKG2D and MIC A molecules in the tumor tissues.
24444073CONCLUSION: These results clearly indicate a safety and usability of hUCMSCs-LV- IL-21 in ovarian cancer gene therapy, suggesting the strategy may be a promising new method for clinical treatment of ovarian cancer.
24445858Genetic association of IL-21 polymorphisms with dilated cardiomyopathy in a Han Chinese population.
24445858Interleukin-21 (IL-21) gene polymorphisms have been previously found to be associated with autoimmune diseases.
24445858This study aimed to assess the role of IL-21 in DCM in a Han Chinese population.
24445858IL-21 plasma levels in patients were higher than those of the control subjects (p = 0.
24446516IL-21 contributes to fatal inflammatory disease in the absence of Foxp3+ T regulatory cells.
24446516To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed the role of IL-21/IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2-dependent Foxp3 regulatory T cells and suffer from a fatal multiorgan inflammatory disease.
24446516Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2(-/-) mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease.
24446516IL-21/IL-21R interactions were also important for the expansion of effector and memory CD8(+) T cells, which were critical for the development of pancreatitis in Il2(-/-) mice.
24446516These findings demonstrate that IL-21 is a major target of immune system regulation.
24465814Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross.
24489092The factors that contribute to the differentiation of this helper cell subset are incompletely understood, although several cytokines including IL-6, IL-21, and IL-12 can promote TFH cell formation.
24489092In contrast, type I IFNs failed to induce IL-21, the signature cytokine for TFH cells.
24491894Th17 lymphocytes produce a number of pro-inflammatory cytokines, such as interleukin (IL)-17A, IL-17F, IL-21, IL-22 and tumor necrosis factor (TNF)-a, and play a key role in mucosal defense against various pathogens.
24505407The induction of a balanced Th1 and Th17 response, together with expression of effector cytokines, such as IFNG, IL2, IL17, IL21 and IL22, could be used as correlates of a protective host response.
24510007Elevated serum IL-21 levels in hantavirus-infected patients correlate with the severity of the disease.
24510007Serum IL-21 concentration was measured using an enzyme-linked immunosorbent assay.
24510007Serum IL-21 levels began to increase in the fever phase when renal damage appeared.
24510007The highest serum IL-21 level was detected in oliguric phase along with the peak degree of urinary renal impairment.
24510007When entering the polyuric phase, with gradual increase in urine and recovered renal function, the serum IL-21 level was observed to fall, returning to normal level after the renal function recovered in the convalescent phase.
24515612IL-21 was applied to study whether it counteracts the function of UCB and APB CD4(+)CD25(+) T cells.
24515612The addition of IL-21, however, counteracted the suppressive function of expanded UCB and APB Tregs.
24550509Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression.
24550509In contrast, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6(-/-) cells, and Th9 differentiation was increased in Il21(-/-) and Il21r(-/-) T cells.
24550509BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21.
24550509Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production.
24551101Third, in vitro studies revealed that Tfh cell-derived IL-21 could promote IL-10 production and Breg cell differentiation.
24553452In this phenomenon, a novel MΦ population, which is functionally distinguishable from M1 and M2 MΦ subsets and possesses unique phenotypes (IL-12(+), IL-1β(high), IL-6(+), tumor necrosis factor (TNF)-α(+), nitric oxide synthase (NOS) 2(+), CCR7(high), IL-10(high), arginase (Arg)-1(-), mannose receptor (MR)(low), Ym1(high), Fizz(low), and CD163(high)), played central roles through the action of IL-6 and transforming growth factor (TGF)-β but not IL-21 and IL-23.
24564507As discussed, overexpression of type I IFN and BAFF on one hand and IL-6 and IL-21 on the other hand are critically involved in the enhanced plasma cell formation in pSS patients.
24595038Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models.
24595038Bioenergetic abnormalities and metabolic dysfunctionoccur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models.
24595038However, whether metabolic dysfunction occurs earlyin ALS pathophysiology linked to different ALS genes remains unclear.
24595038We show that mutant TDP-43 induction of the AMPK phosphatase,protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models.
24595038Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice.
24598455As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6⁺ memory T-helper cells producing IL-17A, IL-17F, IL-21, and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature.
24598455Expression of IL-17A, IL-17F, IL-21, and IL-22 by CD4⁺CD45RO⁺CCR6⁺ T cells (CCR6⁺ cells) was measured with flow cytometry and compared between IFN⁺, IFN⁻ patients and HCs.
24598455In addition, we found significant correlation between B-cell activating factor of the tumor necrosis family (BAFF)-a factor strongly correlating with IFN type I - and IL-21 producing CCR6⁺ cells.
24611989Interleukin-21 (IL-21) participates in tissue damage in various immune-mediated diseases.
24611989The percentages of IL-21(+) CD3(+) CD8(-) and IL-21(+) CD3(+) CD8(+) T cells and the levels of serum IL-21 in CAHB patients were significantly higher than that in the IC, CHC patients and HC (P < 0.
24611989The levels of IL-21 expression in the liver tissues were associated significantly with increased degrees of inflammation and fibrosis in CAHB patients (P < 0.
24615479IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting the motor system, with extramotor involvement to a variable extent.
24615479An autosomal dominant hexanucleotide (GGGGCC) expansion in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent genetic cause of ALS, but its metabolic pattern has not been studied systematically.
24615479OBJECTIVES: To evaluate the use of 18fluorodeoxyglucose-positron-emission tomography as a marker of ALS pathology and investigate whether a specific metabolic signature is present in patients with C9orf72 mutations.
24615479DESIGN, SETTING, AND PARTICIPANTS: In total, 81 patients with a suspected diagnosis of ALS at University Hospital Leuven were prospectively investigated.
24615479ALS was made in 70 of 81 patients.
24615479Of these, 11 were C9orf72 positive and 59 were C9orf72 negative.
24615479ALS cases and 71% of primary lateral sclerosis cases.
24615479Patients who were C9orf72 positive did not differ in survival compared with those who were C9orf72 negative.
24649038Since its discovery in 2000, IL-21 has been the focus of extensive investigation, due to its homology to IL-2, IL-4 and IL-15 and its pleiotropic effects on innate and adaptive immune responses.
24649038An increasing amount of experimental evidence supports a role for IL-21 in the pathogenesis of several allergic diseases, such as allergic rhinitis, atopic dermatitis (AD) and atopic asthma.
24649038In this review, we aimed to discuss the biological characteristics of IL-21 and summarize the current progress on the role of IL-21 in the regulation of allergic inflammation.
24649192VNP20009 and HTV injection of interleukin-21 (IL-21) expression plasmid to evaluate the antitumor potential on an experimental melanoma model.
24649192Moreover, HTV injection of IL-21 plasmid promoted the antitumor activities of VNP20009.
24649192The mice that were administered combined therapy exhibited smaller tumor sizes and longer survival time compared with those administered VNP20009 or IL-21 treatment alone.
24649192IL-21 induced more infiltrating natural killer (NK) and T cells to the tumor area.
24649192IL-21 promotes antitumor immune responses, suggesting a novel strategy in the treatment of cancer.
24669269Serum IL-21 levels associated with chronic hepatitis B and hepatitis B-related liver failure.
24669269IL-21 stimulates T and B cell responses and plays a role in the control of chronic viral infections.
24669269The proportion of T cells producing IL-21 in the peripheral blood was assessed by intracellular cytokine staining and flow cytometry.
24669269Mean serum IL-21 levels in patients with chronic hepatitis B (CHB) and the HCs were 303.
24669269In addition, the mean serum IL-21 level in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF) was 455.
24669269Serum IL-21 levels were highest in the patients with HB-ACLF (455.
24669269The mean serum IL-21 levels in patients with cirrhosis also increased, but there was no statistically significant difference when compared with the HCs (P=0.
24669269The frequency of IL-21+CD4+ cells also increased compared with the HCs and correlated with the number and percentage of lymphocytes in the peripheral blood.
24669269Serum IL-21 levels increased in CHB and HB-ACLF patients.
24669269Relatively low serum IL-21 levels in CHB may have a causal role in the persistence of HBV infection.
24673562Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, plays a key role in regulating inflammation.
24673562Serum level of IL-21 in 92 CAD patients and 73 controls was measured by the enzyme-linked immunosorbent assay.
24673562Data showed that IL-21 expression was significantly increased in CAD than in controls (p < 0.
24673562Interestingly, when comparing IL-21 level with different genders, male subjects revealed higher IL-21 than female subjects (p = 0.
24673562Also, we observed that patients with hypertension had upregulated level of serum IL-21 (p = 0.
24673562Moreover, serum level of IL-21 was positively correlated with total cholesterol level (p = 0.
24673562In addition, we analyzed IL-21 level with the severity of CAD, and identified that cases with 3-vessel affected had significantly elevated level of IL-21 than those with 1-vessel or 2-vessel affected.
24702489The aim of our study was to assess serum levels of IL-21 in patients with recent-onset RA in relation to disease activity and response to treatment.
24702489We analyzed serum levels of IL-21 in 51 RA patients, both before and 12 weeks after the initiation of treatment and in 36 healthy individuals.
24702489We found that IL-21 levels were not increased in patients with recent-onset RA compared with healthy controls, but they had significantly decreased from baseline to week 12 during treatment.
24702489Baseline levels of IL-21 significantly correlated with measures of disease activity (p<0.
24702489Although IL-21 levels did not predict achievement of remission, decrease in IL-21 levels correlated with improvement in disease activity after 12 weeks (p<0.
24703839Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system.
24703839We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations.
24703839SOD1(A4V/+) ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability.
24703839The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases.
24709525The levels of IL-10, and IL-21, and expression of the B cell marker BLNK also decreased significantly after transplantation.
24716897The voltage-gated calcium channel blocker lomerizine is neuroprotective in motor neurons expressing mutant SOD1, but not TDP-43.
24716897Excitotoxicity and disruption of Ca(2+) homeostasis have been implicated in amyotrophic lateral sclerosis (ALS) and limiting Ca(2+) entry is protective in models of ALS caused by mutation of SOD1.
24716897Lomerizine reduced glutamate excitotoxicity in cultured motor neurons by reducing the accumulation of cytoplasmic Ca(2+) and protected motor neurons against multiple measures of mutant SOD1 toxicity: Ca(2+) overload, impaired mitochondrial trafficking, mitochondrial fragmentation, formation of mutant SOD1 inclusions, and loss of viability.
24716897Calcium did not play the same role in the toxicity of these mutant proteins as with mutant SOD1 and lomerizine failed to prevent cytoplasmic accumulation of mutant TDP-43, a hallmark of its pathology.
24716897These experiments point to differences in the pathogenic pathways between types of ALS and show the utility of primary culture models in comparing those mechanisms and effectiveness of therapeutic strategies.
24719360METHODS: We characterized interleukin-21 (IL-21)- producing cells in sf mice.
24719360We examined the underlying mechanisms of enhanced IL-21 production in sf mouse CD4+ T cells.
24719360We examined the roles of IL-21 and CD8+ T cells in autoimmune inflammation in sf mice using IL-21 receptor (IL-21R)-deficient sf mice.
24719360RESULTS: IL-21-producing c-Maf+CD4+ T cells, which were distinct from Th17 cells, were increased in sf mice.
24719360Increased c-Maf expression was involved in enhanced IL-21 production in sf mouse CD4+ T cells.
24719360Experiments using bone marrow chimeric mice showed that lack of cell-extrinsic suppression by FoxP3+ Treg cells, but not cell-intrinsic defects in FoxP3 in sf mouse CD4+ T cells, was mainly involved in the development of IL-21-producing c-Maf+CD4+ T cells in sf mice.
24719360CONCLUSION: Unique IL-21-producing c-Maf+ CD4+ T cells develop in the absence of FoxP3+ Treg cells, induce short-lived effector CD8+ T cells, and enhance multiorgan autoimmune inflammation in sf mice.
24740287Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models.
24740287Bioenergetic abnormalities and metabolic dysfunction occur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models.
24740287However, whether metabolic dysfunction occurs early in ALS pathophysiology linked to different ALS genes remains unclear.
24740287We show that mutant TDP-43 induction of the AMPK phosphatase, protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models.
24740287Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice.
24746753Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.
24746753Functional experiments were performed to assess the effect of IL-21 on the immune system.
24746753Deficiency of IL-21 resulted in reduced numbers of circulating CD19(+) B cells, including IgM(+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers.
24746753In vitro assays demonstrated that mutant IL-21(Leu49Pro) did not induce signal transducer and activator of transcription 3 phosphorylation and immunoglobulin class-switch recombination.
24746753CONCLUSION: Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency.
24746753IBD might mask an underlying primary immunodeficiency, as illustrated here with IL-21 deficiency.
24751819Since its discovery in 2000, a tremendous amount has been learned about its biological actions and the molecular mechanisms controlling IL-21-mediated cellular responses.
24751819IL-21 regulates both innate and adaptive immune responses, and it not only has key roles in antitumour and antiviral responses but also exerts major effects on inflammatory responses that promote the development of autoimmune diseases and inflammatory disorders.
24751819Numerous studies have shown that enhancing or inhibiting the action of IL-21 has therapeutic effects in animal models of a wide range of diseases, and various clinical trials are underway.
24751819The current challenge is to understand how to specifically modulate the actions of IL-21 in the context of each specific immune response or pathological situation.
24751819In this Review, we provide an overview of the basic biology of IL-21 and discuss how this information has been - and can be - exploited therapeutically.
24756111Exploring the IL-21-STAT3 axis as therapeutic target for Sézary syndrome.
24756111STAT3 can be activated by IL-21 in vitro and the IL-21 gene itself is a STAT3 target gene, thereby creating an autocrine positive feedback loop that might serve as a therapeutic target.
24756111CD3/CD28-mediated activation of Sézary cells induced IL-21 expression, accompanied by STAT3 activation and increased proliferation.
24756111Blocking IL-21 in CD3/CD28-activated cells had no effects, whereas Stattic abrogated IL-21 expression and cell proliferation.
24756111In contrast, blocking IL-21 alone seems insufficient to affect STAT3 activation, cell proliferation, or apoptosis.
24757141OBJECTIVE: The cytokine interleukin-21 (IL-21) can have both proinflammatory and immunosuppressive effects.
24757141The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17 cells.
24757141METHODS: Antigen-induced arthritis (AIA) and chronic streptococcal cell wall (SCW) arthritis were induced in IL-21 receptor-deficient (IL-21R(-/-) ) and wild-type mice.
24757141IL-21 stimulation also affected the Toll-like receptor 2 (TLR-2)/caspase recruitment domain 15 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis.
24757141CONCLUSION: In contrast to the proinflammatory role of IL-21 in adaptive immunity, which drives IL-17+IFN+ cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS-1 and SOCS-3.
24757141If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in rheumatoid arthritis.
24789434Interestingly, the elevation of circulating Tfh was negatively correlated with serum IL-21 in DLBCL patients.
24789434In addition, a positive correlation between circulating Tfh and IL-21 receptor on CD + 8 T cells was observed in patients.
24789434This study suggests involvement of circulating Tfh and IL-21 in the pathogenesis and progression of DLBCL and provides a potential target for treating this disease.
24804206Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease.
24804206The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1.
24804206PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1.
24804206These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.
24807637IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses.
24807637BACKGROUND: Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses; however, the exact role it plays in allergic diseases is not well understood.
24807637OBJECTIVE: To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung.
24807637Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production.
24807637Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics.
24807637CONCLUSION: These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production.
24820310BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells.
24835396Human B cells express granzyme B (GrB) when cultured with IL-21, a cytokine overproduced in CD and UC mucosa.
24835396IL-21 enhanced GrB expression in control CD19(+) B cells and increased their cytotoxic activity.
24850724In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4(+) lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3.
24850724Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4(+) T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines.
24858204In this study, we evaluated the production of interleukin-21 (IL-21), a key soluble mediator mainly produced by CD4+ T cells.
24858204The aim of this study was to investigate the role of IL-21 production during the clinical course of primary and secondary DENV infections and the potential association of IL-21 serum levels with the disease pathogenesis.
24858204IL-21 levels were measured using a quantitative capture ELISA assay.
24858204The levels of IL-21 were significantly elevated in the disease group compared with the control group.
24858204IL-21 was detected in primary and secondary DENV infections, with a significantly higher concentration in the convalescent phase of primary infections.
24858204IL-21 levels were significantly higher in patients with secondary acute DHF infections when compared with those with secondary acute DF infection.
24858204There was a relationship between the elevated serum levels of IL-21 and the production of DENV-specific IgM and IgG antibodies.
24858204Taking together, our results show for the first time the involvement of IL-21 during the clinical course of DENV infections.
24858204We speculate that IL-21 may play a protective role in the context of the convalescent phase of primary infections and the acute phase of secondary infections.
24859450Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development.
24891301Furthermore, IL-6 deficiency abrogated differentiation of Th1 and extrafollicular T helper cells, germinal center B cells, and plasma cells in the spleen and eliminated renal T cells with IL-17, interferon-γ, and IL-21 production potential.
24891320However, STAT3 activation is a key oncogenic pathway in natural killer (NK)-lineage large granular lymphomas, and we recently reported enhanced proliferation and function of human NK cells activated with IL-21, which signals primarily through STAT3.
24891320Moreover, NKG2D expression on murine NK cells having conditional STAT3 ablation is lower than on NK cells from wild-type mice, and human NK cells carrying dominant-negative STAT3 mutations have decreased baseline NKG2D expression and blunted responses to IL-10 and IL-21.
24891320Lastly, we show binding of STAT3 to a predicted STAT3 binding site upstream of the NKG2D gene, which is enhanced by IL-10 and IL-21 and decreased by STAT3 inhibition.
24899182Interleukin-6 (IL-6) and IL-21 have been known to play important roles in Tfh cell differentiation.
24899182Enhanced generation of Tfh cells by IL-7-mFc treatment was not significantly affected by the neutralization of IL-6 and IL-21, indicating an independent role of IL-7 on Tfh differentiation.
24909430We recently showed that interleukin-21 (IL-21) promoted Tfh cell differentiation in autoimmune BXD2 mice that develop spontaneous GCs.
24909430This study was undertaken to determine the modulatory effects of IL-21 on Tfr cells and the Tfr cell to Tfh cell balance in BXD2 mice.
24909430The effects of IL-21 on Tfr cells and the Tfr cell:Tfh cell ratio were evaluated.
24909430Recombinant murine IL-21 suppressed FoxP3 and significantly reduced Tgfb1, Il2, and Gitr but enhanced Il21, Il6, Pd1, Cxcr5, and Icos expression in Tfr cells.
24909430IL-21 also counteracted Tfr cell-mediated inhibition of antibody secretion in the Tfh cell-B cell coculture system.
24909430CONCLUSION: Our findings indicate that high levels of IL-21 selectively enhance Tfh cell differentiation but inhibit Tfr cell commitment and the suppressive function of Tfr cells on Tfh cells and B cells, suggesting that IL-21 skews the balance from Tfr cells to Tfh cells to promote autoreactive GC reactions in BXD2 mice.
24921943Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4-PPARγKO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction.
24943738Treatment with anti-IL-21 and anti-interferon (IFN)-γ antibodies abrogated these anti-allergic effects in mice treated with α-GalCer/OVA-BMDCs.
24943738These results suggest that activation of iNKT cells in regional lymph nodes induces anti-allergic effects through production of IL-21 or IFN-γ, and that these effects are enhanced by simultaneous stimulation with antigen.
24944624Association between IL-21 gene rs907715 polymorphisms and Graves' disease in a Southern Chinese population.
24944624Interleukin-21 (IL-21) is a pleiotropic cytokine linking innate and adaptive immune responses, which has been reported to play a key role in multiple autoimmune diseases.
24944624The aim of the present case-control study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of rs907715 within the IL-21 gene and Graves' disease (GD) in a Southern Chinese population.
24944624IL-21 gene rs907715 polymorphisms were detected by direct DNA sequencing.
24944624These observations indicated that polymorphisms of IL-21/rs907715 may affect the susceptibility to GD in a Southern Chinese population.
24950680BACKGROUND AIMS: Interleukin-21 (IL-21) can enhance the effector function of natural killer (NK) cells but also limits their proliferation when continuously combined with IL-2/IL-15.
24950680Paradoxically, membrane-bound (mb)-IL-21 has been shown to improve human NK cell proliferation when cultured with IL-2/mb-IL-15.
24950680To clarify the role of IL-21, we investigated the effect of the timing of IL-21 addition to NK cell culture.
24950680NK cells treated with IL-21 in the "first week" group showed cytotoxicity similar to that in control cells.
24950680On day 28, there was a significant increase in cytotoxicity of "first week" NK cells that received IL-21 treatment for an additional 2 days compared with the "first week" NK cells (P < 0.
24950680CONCLUSIONS: These data suggest that controlling temporal exposure of IL-21 during NK cell proliferation can be a critical consideration to improve the yields and cytotoxicity of NK cells.
24966156Bone marrow mesenchymal stromal cells (MSCs) can modify disease progression in amyotrophic lateral sclerosis (ALS) model.
24966156However, there are currently no accurate biological markers for predicting the efficacy of autologous MSC transplants in ALS patients.
24966156We enrolled 37 patients with ALS who received autologous MSCs via intrathecal injection in two monthly doses.
25007029Interleukin-21 (IL-21), a type I cytokine that is produced by T cells, exerts regulatory effects on a variety of immune cells.
25007029In our previous study, we found that serum levels of IL-21 were significantly decreased in patients with severe atopic dermatitis, suggesting that IL-21 might play a role in allergic reactions.
25007029In this study, we investigated the role of IL-21/IL-21 receptor (IL-21R) in patients with allergic rhinitis.
25007029Our results demonstrated that there was no difference in IL-21 serum levels between allergic rhinitis patients and controls.
25007029IL-21 alone neither induced nor inhibited IgE secretion from CD40L-stimulated B cells.
25007029However, IL-21 inhibited IgE secretion of B cells that were induced by the combination of CD40L and IL-4 in allergic patients.
25007029These results suggest that the role of IL-21 in an ongoing allergic reaction is to downregulate the IgE level by binding to IL-21R on B cells, which increases the expression in allergic patients.
25011937Moreover, the levels of IFN-γ, IL-17, IL-21, IL-22, IL-23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α were diminished.
25053783The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10.
25053783IL-21-deficient mice.
25053783This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role.
25084174Multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE) are characterized by focal inflammatory infiltrates into the central nervous system, demyelinating lesions, axonal damage, and abundant production of cytokines that activate immune cells and damage neurons and oligodendrocytes, including interleukin-12 (IL-12), IL-6, IL-17, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and interferon-gamma.
25092124In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P<0.
25092124Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients.
25101889Notably, in normal but not SLE B cells, interleukin-21 (IL-21) induced PTEN expression and suppressed Akt phosphorylation induced by anti-immunoglobulin M and CD40L stimulation.
25101889However, this deficit was not primarily at the signaling or the transcriptional level, because IL-21-induced STAT3 (signal transducer and activator of transcription 3) phosphorylation was intact and IL-21 up-regulated PTEN mRNA in SLE B cells.
25101889These miRs down-regulated the expression of PTEN, and IL-21 stimulation increased the expression of miR-7 and miR-22 in both normal and SLE B cells.
25111021Poly-A binding protein-1 localization to a subset of TDP-43 inclusions in amyotrophic lateral sclerosis occurs more frequently in patients harboring an expansion in C9orf72.
25111021Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease in which the loss of spinal cord motor neurons leads to paralysis and death within a few years of clinical disease onset.
25111021In almost all cases of ALS, transactive response DNA binding protein of 43 kDa (TDP-43) forms cytoplasmic neuronal inclusions.
25111021ALS is fused in sarcoma, an RNA binding protein that also forms cytoplasmic inclusions in spinal cord motor neurons.
25111021We report on the colocalization of PABP-1 to both TDP-43 and fused-in-sarcoma inclusions in 4 patient cohorts: ALS without a mutation, ALS with an intermediate polyglutamine repeat expansion in ATXN2, ALS with a GGGGCC hexanucleotide repeat expansion in C9orf72, and ALS with basophilic inclusion body disease.
25111021Notably, PABP-1 colocalization to TDP-43 was twice as frequent in ALS with C9orf72 expansions compared to ALS with no mutation.
25111021This study highlights PABP-1 as a protein that is important to the pathology of ALS and indicates that the proteomic profile of TDP-43 inclusions in ALS may differ depending on the causative genetic mutation.
25112467IL-17RA is upregulated by some proinflammatory cytokines such as IL-21 and IL-15 and downregulated by IL-2, while the effect of IL-1β, IL-6, IL-8, TNF-α on IL-17RA expression in non-small cell lung caner (NSCLC) remains unknown.
25126827Interleukin-21 (IL-21) is a recently discovered cytokine and plays critical roles in antitumor immune responses.
25126827In this study, we investigated the association between IL-21 genetic polymorphisms and the susceptibility to DLBCL, and the possible functions of these polymorphisms.
25126827Two IL-21 polymorphisms, rs907715G/A and rs2221903A/G, were examined in 212 DLBCL patients and 232 healthy controls.
25126827Moreover, we investigated the correlation between IL-21 polymorphisms and serum level of IL-21.
25126827Results showed that subjects carrying rs907715AA had significantly increased level of IL-21 than those with GG genotype or GA genotype.
25126827These data suggest that rs907715G/A polymorphism may act as a protective factor of DLBCL and might affect the serum level of IL-21.
25129403We aimed to investigate the distribution of Th17 cells, the expressions of Th17-related cytokines (IL-17, IL-21 and IL-22) and their association with disease activity in IBD patients.
25129403RESULTS: Compared with healthy controls, the number of Th17 cells and the expressions of IL-17, IL-21 and IL-22 were significantly increased in active IBD patients (P < 0.
25129403CONCLUSIONS: Th17 cells and Th17-related cytokines (IL-17, IL-21 and IL-22) were increased in the intestinal mucosa in active IBD patients and may play an important role in disease activity and mucosal damage.
25138204Our data also demonstrated that intravenous transfer of LPS-treated DCs blocks experimental autoimmune encephalomyelitis (EAE) development and down-regulates expression of retinoic acid-related orphan receptor gamma t (ROR-γt), interleukin (IL)-17A, IL-17F, IL-21, IL-22 and interferon (IFN)-γ in myelin oligodendrocyte glycoprotein (MOG)-primed CD4(+) T cells in the peripheral environment.
25149304The most utilized Elispot assay is the interferon-gamma (IFN-γ) test, a marker for CD8(+) CTL activation, but Elispot can also be used to distinguish different subsets of activated T cells by using other cytokines such as T-helper (Th) 1-type cells (characterized by the production of IFN-γ, IL-2, IL-6, IL-12, IL-21, and TNF-α), Th2 (producing cytokines like IL-4, IL-5, IL-10, and IL-13), and Th17 (IL-17) cells.
25174402However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6.
25174402Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells.
25174402IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation.
25177353There were similar frequencies of Th characterized cytokine production such as IL-21, IFN-γ, IL-4, IL-17 or IL-22 in aged and young Tfh cells.
25177353However, aged PBMCs produced a significantly higher amount of IL-21 compare to young subjects.
25192845Protective efficacy of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) adjuvated with recombinant IL-15 and IL-21 against experimental toxoplasmosis in mice.
25192845RESULTS: Immunization with pVAX-CDPK1 or pVAX-IL-21-IL-15 alone developed strong humoral responses and Th1 type cellular immune responses, and the significantly (P < 0.
25192845Co-injection of pVAX-IL-21-IL-15 significantly increased humoral and cellular immune responses compared to the group of pVAX-CDPK1 or pVAX-IL-21-IL-15.
25192845Challenge experiments showed that co-administration of pVAX-IL-21-IL-15 and pVAX-CDPK1 significantly (P < 0.
25192845VAX-IL-21-IL-15 (12.
25192845VAX-IL-21-IL-15 + pVAX-CDPK1 significantly reduced the number of brain cysts (72.
25192845VAX-IL-21-IL-15 alone (43.
25194055Aberrant upregulation of IL-21 in CD4(+) T cells expressing mutant Ikaros was responsible, at least in part, for the enhanced IL-22 expression in a Stat3-dependent manner.
25211639Thus, we aimed to investigate the ability of IL-21 in the regulation of middle version of HBV envelop protein (MS) DNA vaccine.
25211639Fusion plasmid encoding IL-21 linked with MS was constructed.
25211639Furthermore, the level of circulating HBsAg was decreased by induction of anti-HBs antibody and HBsAg-specific CD8+ T-cell response to both pcDNA-IL-21/S2S and pcDNA-S2S vaccination in HBV transgenic mice.
25211639But IL-21 did not strengthen immune response induced by HBV DNA immunization.
25213598However, the pathogenic mechanism of TDP-43 in ALS is unclear.
25213598To determine the association between TDP-43 and neurotoxicity in an ALS model, we characterized TDP-43 expression in hSOD1(G93A) transgenic mice (Tg) as an ALS animal model.
25213598In addition, the expression of phosphorylated and truncated TDP-43 increased in the SP of ALS mice compared with age-matched non-Tg.
25213598These findings suggest that modified TDP-43 may be involved in motor neuron death in the SP of a SOD1(G93A)-expressing familial ALS (fALS) animal model.
25232056In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients.
25243187The level of sera IL-21 was examined; 24 h urinary protein and eGFR were calculated.
25243187RESULTS: The frequency of circulating CD4(+)CXCR5(+), CD4(+)CXCR5(+)ICOS(+), and CD4(+)CXCR5(+)PD-1(+) TFH cells and the levels of sera IL-17A, IFN-γ, IL-2, IL-10, IL-4, and IL-21 were significantly higher in MCD patients (P < 0.
25243187CD4(+)CXCR5(+)PD-1(+) TFH cells were correlated positively with the levels of serum IL-21 (r = 0.
25243187Also, the percentages of CD4(+)CXCR5(+)ICOS(+) TFH cells were correlated positively with the levels of serum IL-21 (r = 0.
25243187Following standard therapies, the percentages of circulating CD4(+)CXCR5(+), CD4(+)CXCR5(+)PD-1(+), and CD4(+)CXCR5(+)ICOS(+) TFH cells and the levels of serum IL-21 were significantly reduced, but the levels of serum IL-4 and IL-10 were increased (P < 0.
25243706In the present study, the levels of serum IL-21 in 77 patients with various degrees of CHB in immune clearance phase (IC), 25 patients infected with hepatitis B virus (HBV) in immune tolerance phase (IT), and 25 healthy controls (HC) were measured and their potential association with major clinic indexes was examined.
25243706Peripheral blood mononuclear cells from CHB patients were stimulated with hepatitis B core antigen (HBcAg) in the presence or absence of anti-IL-21 antibody or recombinant IL-21, and the frequency of HBcAg-specific IL-21(+)CD4(+) and interferon (IFN)-γ(+)CD8(+) T cells was characterized by flow cytometry.
25243706Our data indicated that the levels of serum IL-21 were significantly higher in the IC CHB patients than that in the other groups and were positively correlated with the levels of serum HBV DNA and HBeAg in the IC patients.
25243706There was a low frequency of HBcAg-specific IL-21(+)CD4(+) T cells in IC CHB patients.
25243706Further, IL-21 enhanced HBcAg-specific IFN-γ(+)CD8(+) T cell proliferation, while treatment with anti-IL-21 inhibited antigen-specific IFN-γ(+)CD8(+) T cell expansion in vitro.
25243706Our findings imply that IL-21 positively regulates proinflammatory IFN-γ(+)CD8(+) T cell responses during the process of chronic HBV infection in humans.
25245953Moreover, serum IL-10 and IL-21 concentrations were significantly lower in RA patients compared to healthy controls (P < 0.
25245953CD19(+)CD5(+)GzmB(+) B cells did not correlate with DAS28, IL-21, or GzmB (P > 0.
25245953Interestingly, IL-21 and GzmB levels positively correlated in RA patients (P < 0.
25258142TH1/TFH cells coexpress the TH1 and TFH effector cytokines IFN-γ and IL-21 and the TFH marker CXCR5, demonstrating that the coexpressed TH1 and TFH subset-specifying transcription factors T-box transcription factor (T-bet) and B cell lymphoma 6 are both functionally active.
25258142IL-6 and IL-12 controlled respective expression of IL-21 and IFN-γ, with IL-21 being key for humoral immunity.
25258142Induction of a T-cell subset coexpressing IL-21 and IFN-γ might combine IL-21-mediated T-cell aid for antibody production while maintaining TH1 cytokine expression to support other cellular immune defenses.
25258700These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease.
25263220We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis.
25263533In response to IL-2, these CD25(+) Tfh cells increased expression of costimulatory molecules ICOS or OX40, upregulated transcription factor cMaf, produced cytokines IL-21, IL-17, and IL-10, and raised the levels of antiapoptotic protein Bcl2.
25265199Furthermore, Th17-related cytokines CCL20, IL-17A, IL-6 and IL-21 were all increased in the kidneys of IgAN mice.
25301201Cells were stained for Th17 cytokines and their receptors (IL-17A, IL-17F, IL-21, IL-22, IL-17R, and IL-23R) using flow cytometry.
25301201Cytokine concentrations from cell culture supernatants were quantified using a multiplex assay for IL-17A, IL-17F, IL-21, IL-22, and IL-23.
25301201There was also a significant reduction in IL-21-positive cells following allergen challenge from 3.
25321844Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency.
25321844PURPOSE OF REVIEW: This review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) deficiencies as novel entities of primary immunodeficiency.
25321844SUMMARY: Human IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common variable immunodeficiency.
25321844In view of the critical role of IL-21 in controlling immune homeostasis, early hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children.
25328554These genes include HLA genes, STAT4, CD247, TBX21, PTPN22, TNFSF4, IL23R, IL2RA, IL-21, SCHIP1/IL12A, CD226, BANK1, C8orf13-BLK, PLD4, TLR-2, NLRP1, ATG5, IRF5, IRF8, TNFAIP3, IRAK1, NFKB1, TNIP1, FAS, MIF, HGF, OPN, IL-6, CXCL8, CCR6, CTGF, ITGAM, CAV1, MECP2, SOX5, JAZF1, DNASEIL3, XRCC1, XRCC4, PXK, CSK, GRB10, NOTCH4, RHOB, KIAA0319, PSD3 and PSOR1C1.
25330859Transplantation of a mixture of such MPC populations (MPC-MIX) into the hind legs of SOD1 G93A transgenic mice (SOD1 mice), the commonly used model of ALS, delayed the onset of disease symptoms by 30 days and prolonged the average lifespan by 13 days.
25330859The results suggest that long-term delivery of a mixture of several NTFs by the transplantation of engineered MPC has a beneficial effect in the ALS mouse model.
25337212IL-22 plays the important role in the pathogenesis of CRS, and further research is needed to understand the complex interactions with other cytokines and the exact mechanism of transcriptional regulation for IL-22.
25345823The frequency of peripheral blood FOXP3+CXCR5+CD4+TFR cells, CXCR5+CD4+TFH cells, the ratio of FOXP3+CXCR5+CD4+TFR/CXCR5+CD4+TFH cells and the concentration of serum IL-21 in the AS patients were significantly higher than those in the healthy controls (P < 0.
25345823IL-21 decreased after treatment (P = 0.
25345823TFR cells was negatively correlated with that of TFH cells and the concentration of serum IL-21 after treatment (r = -0.
25351608Interleukin-21 (IL-21) reduces allergic symptoms in murine models and inhibits IL-4-induced IgE secretion by B cells.
25351608However, whether or not IL-21 directly affects Th2 cells, which leads to reduced allergic symptoms, is unclear.
25351608In this study, we investigated the effects of IL-21 on the differentiation and effector functions of Th2 cells.
25351608We found that IL-21 reduced the number of differentiated Th2 cells and these Th2 cells showed a diminished Th2 cytokine production.
25351608Intranasal administration of IL-21 at the beginning of ovalbumin (OVA) sensitization or before OVA challenge decreased Th2 cytokines in the bronchoalveolar lavage fluid of OVA/alum-immunized allergic mice.
25351608In addition, the inhibitory effects of IL-21 on Th2 effector functions can also be found in allergic patients.
25351608Our results demonstrate that IL-21 suppresses the development of Th2 cells and functions of polarized Th2 cells.
25351608Hence, the administration of IL-21 may be considered for use as a preventive and therapeutic approach when dealing with Th2-mediated allergic diseases.
25352130The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.
25352130Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production.
25354343While the cellular sources of IL22 have yet to be identified, the HUC cytokine and chemokine profiles support the concept that IL22-producing cells are present in the human bladder mucosa tissue and that IL22 plays a regulatory role in HUC functions.
25385601Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism.
25385601Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro.
25385601Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients.
25398236OBJECTIVES: We investigated the roles of bystander T, B, and NK cells; NKT cell-derived interferon-γ, interleukin (IL)-4, and IL-21 cytokines; and NKT cell-derived perforin and granzyme B cytotoxins in promoting CD4(+) NKT cell atherogenicity.
25398236To investigate the role of NKT cell-derived interferon-γ, IL-4, and IL-21 cytokines and perforin and granzyme B cytotoxins, CD4(+) NKT cells from mice deficient in these molecules were transferred into NKT cell-deficient ApoE(-/-)Jα18(-/-) mice.
25398236CD4(+) NKT cells deficient in IL-4, interferon-γ, or IL-21 augmented atherosclerosis in ApoE(-/-)Jα18(-/-) mice by ≈95%, ≈80%, and ≈70%, respectively.
25404049Intraperitoneal administration of WA at a dosage of 4 mg/kg of body weight was initiated from postnatal day 40 until end stage in SOD1(G93A) mice, and from 9 months until end stage in SOD1(G37R) mice.
25404049The beneficial effects of WA in the SOD1(G93A) mice model were accompanied by an alleviation of neuroinflammation, a decrease in levels of misfolded SOD1 species in the spinal cord, and a reduction in loss of motor neurons resulting in delayed disease progression and mortality.
25404049Interestingly, WA treatment triggered robust induction of heat shock protein 25 (a mouse ortholog of heat shock protein 27), which may explain the reduced level of misfolded SOD1 species in the spinal cord of SOD1(G93A) mice and the decrease of neuronal injury responses, as revealed by real-time imaging of biophotonic SOD1(G93A) mice expressing a luciferase transgene under the control of the growth-associated protein 43 promoter.
25415378High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time.
25415378Eleven of the patients carried mutations in C9orf72 and seven in SOD1.
25415378Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls.
25415378We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.
25440607Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies.
25481744We identified IL-2 and IL-15 as key molecular determinants in this process and excluded a major function for IL-4, IL-7 and IL-21.
25485537Th17 cells and Treg cells were measured by flow cytometry and IL-17, IL-21, and IL-10 secretion by enzyme immunoassay technique.
25485537In untreated cultured PBMCs from ITP patients, we observed elevated Th17 cell and IL-21 levels and RORγt mRNA expression, decreased Treg cells and Foxp3 mRNA expression, and an increased ratio of Th17/Treg and RORγt/Foxp3.
25485537However, no significant difference was found for Treg cells and Foxp3 mRNA expression, RORγt/Foxp3 ratio, and IL-21 and IL-10 levels after DAPT treatment in ITP patients.
25500255RESULTS: The RT-qPCR analysis showed a significantly higher expression of IL-17A, IL-21, IL-22, IL-26, IL-17RA, IL-21R, and IL-22R1 mRNA; consistently, the IHC analysis showed an over-expression of IL-17RA, IL-21R and IL-22R1 and the Western blotting analysis showed an over-expression of IL-17A, IL-21, IL-21R and IL-22R1 in early SSc skin lesions.
25500255The mRNA levels of IL-21 were higher in diffuse cutaneous than limited cutaneous SSc lesions.
25500255The mRNA expression of IL-26, IL-22, IL-22R1, mRNA and protein expression of IL-17A, IL-21, IL-21R were positively correlated with the modified Rodnan skin score of SSc.
25500255In addition, the mRNA levels of ICAM-1 were positively correlated with IL-17A/IL-17RA, and VEGFA and IL-4 were both positively correlated with IL-21/IL-21R, while TGF-β were moderately negatively correlated with IL-22/IL-22R1.
25500255IL-21/IL-21R could act as potential biomarkers presenting early SSc skin lesions severity.
25505948IL-21 Modulates Activation of NKT Cells in Patients with Stage IV Malignant Melanoma.
25505948Interleukin-21 (IL-21) is a common γ-chain cytokine produced by T helper and natural killer T (NKT) cells.
25505948Owing to its potent anti-tumor function in preclinical studies and its ability to induce cytotoxicity and interferon-γ (IFN-γ) production in NK and CD8 T cells, recombinant IL-21 (rIL-21) was fast-tracked into early-phase clinical trials of patients with various malignancies.
25505948These results highlight that IL-21 is a potent regulator of NKT cell function in vivo.
25510901Th17 cells are characterized by the expression of effector cytokines IL-17A, IL-17F, IL-21 and IL-22, and lineage specific transcription factor ROR-C in human and ROR-γt in mice.
25510901Generation and differentiation of Th17 cells from naive CD4(+) T cells is driven by transforming growth factor (TGF)-β, IL-6, IL-23, IL-1β and IL-21.
25547181On week 2, 12 and 24 post initial injection, the percentage of splenic Th22 cells, the levels of plasma IL-22, cardiac IL-22 receptor (IL-22R) expression, and indicators of myocardial fibrosis were measured.
25547181The collagen volume fraction (CVF), the percentage of splenic Th22 cells, plasma IL-22 levels, cardiac IL-22R expression and indicators of myocardial fibrosis were then monitored.
25547181RESULTS: Compared to control mice at the same time points, AVMC, chronic myocarditis and DCM mice have higher percentage of splenic Th22 cells, higher plasma IL-22 levels, increased cardiac IL-22R, as well as increased collagen typeI-A1 (COL1-A1), collagen type III-A1 (COL3-A1) and matrix metalloproteinase-9 (MMP9) expression.
25547181The percentage of splenic Th22 cells, plasma IL-22 levels and cardiac IL-22R expression also decreased in anti-IL-22 Ab treatment group as compared to IgG and PBS treated groups of AVMC and chronic myocarditis mice.
25547965Concurrently, thymic cytokine (interleukin-1 beta (IL-1β), interleukin-2 (IL-2), interleukin-10 (IL-10), interleukin-12 p35 subunit (IL-12p35), interleukin-12 p40 subunit (IL-12p40), interleukin-21 (IL-21), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), thymosin β4, thymosin β10, and thymosin β15) mRNA expression levels were decreased.
25548251IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.
25574237In addition, the levels of Th17 cells were found to positively correlate with TGF-β and IL-21 levels.
25575696The role of IL-21 in immunity and cancer.
25575696Interleukin-21 (IL-21), produced predominantly by CD4+ T cells and natural killer T (NKT) cells, is a newly discovered member of the common γ-chain family of cytokines.
25575696In recent years, the role for IL-21 in the pathogenesis of cancer has also been extensively studied.
25575696In this review, we will discuss recent advances concerning the role of IL-21 in immunological processes and the pathogenesis of cancer.
25611428Previously, we showed that IL-21 significantly inhibits the CpG-mediated proliferation of CLL B cells in progressive compared to nonprogressive patients.
25617881METHODS: The levels of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40L and TNF-α were measured in the CSF and plasma in age-matched subjects with NPH (n=20) and controls (n=20) by multiplex assay.
25627620Herein, we report that elevations of both serum and intrahepatic interleukin-21 (IL-21) were found in patients with PBC and, in particular, promoted B-cell proliferation, signal transducer and activator of transcription 3 phosphorylation and AMA production in vitro.
25627620More important, upon stimulation with recombinant E2 subunit of pyruvate dehydrogenase complex, CXCR5(+) CD4(+) T cells in PBC produced higher levels of IL-21 than healthy controls.
25627620CONCLUSION: CXCL13 promotes aggregation of CD19(+) B cells and CXCR5(+) CD4(+) T cells, which directs the aberrant AMA response by IL-21.
25627812Importantly, although interleukin (IL)-23 is critical, IL-12 and IL-21 are dispensable for protective Th17 recall responses.
25644114Finally, GzmB(+) B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21(+) T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place.
25644850Both antibiotic regimens significantly reduced IL-17A, IL-21, IL-22 and IFN-γ mRNA levels in the terminal ileum but had limited effect on the GI fungal microbiome.
25644850IL-21 expression.
25661862METHODS: We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation.
25661862The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells.
25661862Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation.
25661862CONCLUSIONS: Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy.
25678563PPIA regulates expression of known TARDBP RNA targets and is necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein complexes.
25678563Our data suggest that perturbation of PPIA/TARDBP interaction causes 'TDP-43' pathology.
25678563Moreover, PPIA depletion induces TARDBP aggregation, downregulates HDAC6, ATG7 and VCP, and accelerates disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
25678563Targeting the PPIA/TARDBP interaction may represent a novel therapeutic avenue for conditions involving TARDBP/TDP-43 pathology, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
25689070Furthermore, compared with healthy controls, the function of circulating CXCR5+CD4+ T cells in HCC was impaired, with reduced IL-21 secretion and dysfunction in promoting B cell maturation.
25689841NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor RORγT (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10.
25720411Loss of TDP-43 Inhibits Amyotrophic Lateral Sclerosis-Linked Mutant SOD1 Aggresome Formation in an HDAC6-Dependent Manner.
25720411Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, and progressive neurodegenerative disorder with no cure.
25720411Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS; and aggresome formation of misfolded SOD1 is closely associated with ALS pathogenesis.
25720411In this study, we found that in a cellular model with impaired proteasome activity, the TAR DNA-binding protein 43, which is closely linked with ALS and associated with various neurodegenerative disorders such as frontotemporal lobar degeneration, Alzheimer’s disease, and Parkinson’s disease, can regulate mutant SOD1 aggresome formation through an HDAC6-dependent manner.
25720411TDP-43 deficiency did not affect poly-ubiquitination of mutant SOD1, whereas it greatly decreased the expression level of HDAC6, which is required for aggresome formation of ALS-linked mutant SOD1.
25720411Moreover, overexpression of siRNA-resistant HDAC6 restored mutant SOD1 aggresome formation in TDP-43-knockdown cells.
25720411Thus, our data provide evidence that TDP-43 plays an important role in mutant SOD1 aggresome formation through its regulation of HDAC6.
25743474Time-course analysis of splenic IL-17(+)CD4(+) cell frequencies, the proximal aorta lesion area, serum IL-17, IL-6, TGF-β and IL-1β levels, the mRNA expression of Th17-related molecules such as IL-1β, IL-6, IL17RA, STAT3, IL-21, IL-23, TGF-β and RORγt, Th17-related microRNA levels and the levels of AIM-2, Mincle and NLRP3 were examined.
25743474The gene expression of IL-1β, IL-6, IL-17RA, IL-21, IL-23, TGF-β, STAT3, RORγt, AIM-2, Mincle and NLRP3 was also time dependently stimulated in the aorta of Aa-challenged mice.
25747793Trout ACKR2 expression can be modulated in vivo by bacterial and parasitic infections, and in vitro by PAMPs (poly I:C and peptidoglycan) and cytokines (IL-6, TNF-α, IFN-γ and IL-21) in a time dependent manner.
25758713Multiple effects of IL-21 on human NK cells in ex vivo expansion.
25758713Similar to IL-2 and IL-15, IL-21 is a common γ-chain cytokine that is important in NK cell activation, maturation and proliferation.
25758713The present study aims to assess the effects of membrane-bound and soluble IL-21 on primary human NK cells during ex vivo expansion.
25758713IL-21 was found to have multiple effects on NK cells, increasing their cytotoxicity in a concentration-dependent manner by up-regulating IFN-γ and Granzyme-B expression.
25758713Nevertheless, at a high concentration (50 ng/mL), IL-21 curtailed the life span of NK cells by significantly inducing apoptosis.
25758713Moreover, when treated with IL-21, the number of NKT (CD56(+)CD3(+)) cells increased among peripheral blood mononuclear cells (PBMCs) during ex vivo expansion in a concentration-dependent manner.
25758713IL-21 also promoted expanded cells to enter into S phase of the cell cycle during the first to second weeks of culture.
25758713All these results suggest that IL-21 has multiple effects on NK cell development and functions.
25758713More attention should be given to the dosage and multiple effects of IL-21 when it was applied to NK cells in ex vivo expansion.
25774942Interleukin (IL)-21 has been suggested to play an important role in HBV infection, but it remains unknown whether IL-21 can inhibit HBV replication or how it inhibits HBV replication.
25774942METHODS: In this study, we investigated the influence of IL-21 on HBV replication based on human hepatoma Huh7.
25774942PBMCs) and the possible correlation among IL-21, interferon-γ, tumour necrosis factor-α and IL-10.
25774942RESULTS: We demonstrated that the decrease of IL-21 expression and the increase of IL-10 expression in PBMCs could promote HBV replication in vitro.
25774942We further revealed that IL-21 is not only able to effectively suppress HBV replication directly but also reduce HBV replication by inhibition of IL-10 secretion.
25776751The expression of IL-21, IL-23, IL-17, and retinoic acid receptor-related orphan receptor C (Rorc) was upregulated in GTF-activated VIC, which may enhance the proliferation of memory Th17 cells in an IL-6-dependent manner.
25776751CXCL1-expressing VIC and infiltrating neutrophils could be detected in infected valves, and serum concentrations of IL-17, IL-21, and IL-23 were increased in patients with IE compared to healthy donors.
25776751Furthermore, elevated serum IL-21 levels have been significantly associated with severe valvular damage, including rupture of chordae tendineae, in IE patients.
25778888Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of Th17 related cytokines interleukin-17 (IL-17), IL-21, IL-22, IL-23 and IL-27 in peripheral blood plasma.
25778888The levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to health controls while IL-22 was down-regulated (P<0.
25778888Higher expression of IL-17, IL-21, IL-23, IL-27, miR-181a/b and lower expression of miR-15a/16,miR-34a,miR-194 and IL-22 were observed in the end stage than the early stage of MM patients (P<0.
25778888CONCLUSION: Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients.
25780036CD4+ T cell-derived IL-21 and deprivation of CD40 signaling favor the in vivo development of granzyme B-expressing regulatory B cells in HIV patients.
25780036IL-21 can induce both plasma cells and regulatory B cells.
25780036When culturing such IL-21(+)CD40L(-) Th cells with B cells, the former directly induce B cell differentiation into GraB cells.
25780036In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21-dependent B cell differentiation.
25793261IL22/IL-22R pathway induces cell survival in human glioblastoma cells.
25793261Interleukin-22 (IL-22) is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1) and IL-10R2.
25793261Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies.
25793261Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.
25819349However, little is known about IL-21 function in canine NK cells because the phenotype of these cells remains undefined.
25819349In this study, we selectively expanded non-B and non-T large granular NK lymphocytes (CD3(-)CD21(-)CD5(-)CD4(-)TCRαβ(-)TCRγδ(-)) ex vivo from the peripheral blood mononuclear cells (PBMCs) of healthy dogs using a combination of IL-2, IL-15, and IL-21 in the presence of 100 Gy-irradiated K562 cells.
25819349NK cells proliferated rapidly in response to activation by IL-21 for 3 weeks, and IL-21 was able to induce changes in the mRNA expression of NK cell-related receptors and enhance the effector function of NK cells in perforin- and granzyme-B-dependent manners.
25819349The duration, frequency and timing of IL-21 stimulation during culture affected the rate of proliferation, patterns of receptor expression, cytokine production, and anti-tumor activity.
25819349The optimal conditions for maximizing the IL-21-induced proliferation and effector function of NK cells in the presence of IL-2 and IL-15 were seen in cells treated with IL-21 for the first 7 days of culture but without any further IL-21 stimulation other than an additional 2-day treatment prior to harvesting on day 21.
25819349The results of this study suggest that synergistic interactions of IL-21 with IL-2 and IL-15 play an important role in the proliferation, receptor expression, and effector function of canine NK cells.
25819934Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders.
25819934These disorders also include amyotrophic lateral sclerosis (ALS), a degenerative disease produced by the damage of the upper and lower motor neurons leading to muscle denervation, atrophy and paralysis.
25819934The present study represents the first attempt to investigate the endocannabinoid system in an alternative model, the transgenic mouse model of TAR-DNA binding protein-43 (TDP-43), a protein related to ALS and also to frontotemporal dementia.
25838422Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation.
25838422Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2-associated X protein ratio.
25839161Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man.
25839161IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells.
25839161Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival.
25839161In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells.
25839161IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size.
25839161IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice.
25887296LLDT-8 inhibited IL-1β, IL-6, IL-21 and IL-23 secretion, but promoted the secretion of IL-10 in the supernatants of PBMCs and SFMCs.
25903148We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture.
25903148Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days.
25903148IL-21 and IL-7/15/21 increased CD8+ cells compared to IL-2 or IL-7/15.
25903148IL-21 preferentially expanded a CD8+CD44-CD62L+ T "naïve" population, whereas IL-7/15/21 increased CD8+CD44+CD62Lhigh central-memory T cells.
25903148The addition of IL-21 to IL-7/15 induced greater expansion of lymphocytes in culture and increased the yield of CD8+ T central-memory cells vs.
25907990Thus, prion-like features of amyloid β peptide and tau present in AD, α-synuclein in PD, SOD-1, TDP-43 and others in ALS and serum α-amyloid (SAA) in systemic AA amyloidosis will be reviewed through models available for each disease.
25922848As an independent substudy of the 24-week, randomized, double-blinded CWP-TCZ301 trial of TCZ in RA patients with an inadequate response to disease-modifying antirheumatic drugs, serum levels of cytokines including tumor necrosis factor-alpha, IL-17A, IL-21, IL-23, IL-6, and soluble IL-6 receptor were measured.
25940956However, the contribution of TNFα to the development of ALS is still debated.
25940956We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo.
25940956Since the sciatic nerves of SOD1-G93A/TNFR2-/- mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons.
25940956Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology.
25941359Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1.
25941359Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs.
25941359In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype.
25941359Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation.
25941359Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling.
25942599When orally administered twice-daily, SM934 significantly prolonged the life-span of MRL/lpr mice, ameliorated the lymphadenopathy symptoms and decreased the levels of serum anti-nuclear antibodies (ANAs) and of the pathogenic cytokines IL-6, IL-10 and IL-21.
25944714Additionally, transforming growth factor-β1 (TGF-β1) and interleukin-21 (IL-21) mRNA in CD4(+) T cells and IgA(+) and IgM(+) in PP B cells, as well as intestinal mucosal injury and sIgA levels, were assessed.
25944714Importantly, decreased PD-1/PD-L1 expression was correlated with increased mucosal injury and decreased IgA levels, as well as with decreased TGF-β1 and IL-21 expression.
25976230Neutralizations of IL-17A and IL-21 regulate regulatory T cell/T-helper 17 imbalance via T-helper 17-associated signaling pathway in immune thrombocytopenia.
25976230The effects and mechanisms of IL-17A and IL-21 in Treg/Th17 imbalance and ITP pathophysiology are not clarified.
25976230METHODS: Peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells from ITP patients and healthy controls were treated with cytokines or antibodies to increase or neutralize IL-17A or IL-21 levels for 72 h.
25976230IL-17A or IL-21 increased Th17, decreased Tregs and downregulated Treg/Th17 in vitro.
25976230Conversely, neutralization of IL-17A or IL-21 decreased Th17, increased Tregs and up-regulated Treg/Th17.
25976230The reverse effects of IL-17A or IL-21 were mediated by Th17-associated transcriptional factors.
25976230IL-17A or IL-21 enhanced STAT-1, STAT-3, STAT-5 or RAR-related orphan receptor C (RORC), whereas anti-IL-17A or anti-IL-21 mAb downregulated STAT-1, STAT-5 or RORC transcripts in ITP PBMCs.
25976230IL-21 inhibited apoptosis in ITP PBMCs.
25976230CONCLUSION: IL-17A and IL-21 induce Th17 and inhibit Tregs re-differentiation via Th17-associated signaling pathway in ITP patients in vitro.
25989153Serum cytokine levels (interleukin-4 [IL-4], IL-10, IL-21, and IL-33) were measured by cytometric bead array or enzyme-linked immunosorbent assay.
25994220Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group.
26030772Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry.
26034206CD4⁺CD28null T lymphocytes resemble CD8⁺CD28null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients.
26034206The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21.
26034206Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes.
26034206Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects.
26034206Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15.
26034206Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes.
26034206IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.
26043171Interleukin-21 (IL-21) is a class I cytokine that belongs to the γc-subfamily of cytokines and regulates immune responses.
26043171We recently described the structure of the IL-21R:IL-21 complex and showed that the first tryptophan of the WS motif of IL-21R is mannosylated and involved in formation of a sugar bridge that connects the two FNIII domains of the receptor.
26043171Here, we report the structure of IL-21R alone, which shows that the sugar bridge forms independently of whether IL-21R binds IL-21 or not, and we furthermore investigate the role of this bridge in the export of IL-21R and γC to the plasma membrane.
26044557OBJECTIVE: How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood.
26044557C9orf72(fl/fl) mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells.
26044557Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization.
26044557RESULTS: Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival.
26055806Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 production in systemic lupus erythematosus.
26055806METHODS: The signaling capacity of IL-21 was quantified by stimulating peripheral blood mononuclear cells (PBMCs) with IL-21 and measuring phosphorylation of STAT3 (pSTAT3) in CD4+ T cells, B cells, and natural killer cells.
26055806Induction of miR-155 by IL-21 was investigated by stimulating purified CD4+ T cells with IL-21 and measuring miR-155 expression levels.
26055806The functional role of miR-155 was assessed by overexpressing miR-155 in PBMCs from SLE patients and healthy controls (HCs) and measuring its effects on STAT3 and IL-21 production in CD4+ and CD8+ T cells.
26055806RESULTS: Induction of pSTAT3 in CD4+ T cells in response to IL-21 was significantly decreased in SLE patients compared to HCs (p < 0.
26055806Finally, overexpression of miR-155 in CD4+ T cells increased STAT3 phosphorylation in response to IL-21 treatment (p < 0.
26055806IL-21 production in SLE patients compared to HCs (p < 0.
26055806CONCLUSION: We demonstrate that SLE patients have reduced IL-21 signaling capacity, decreased miR-155 levels, and increased SOCS1 levels compared to HCs.
26056941IRE1 activity using the small luciferase NanoLuc: Evaluation of ALS-related genetic and pathological factors.
26056941Using this technique, we evaluated the effects of several genetic and pathological factors associated with the onset and progression of amyotrophic lateral sclerosis (ALS) on NanoLuc reporter activity.
26056941Under our experimental conditions, inhibition of ER-Golgi transport by the overexpression of mutant Sar1 activated luciferase activity, whereas the co-expression of mutant SOD1 or the C-terminal fragment of TDP-43 (TDP-25) did not.
26067594Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment.
26067594However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated.
26067594We found that the Notch pathway was activated in in vitro and in vivo models of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c.
26067594We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone.
26067594Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.
26097207However, whether IL-21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models.
26097207CONCLUSION: Our results highlight the importance of IL-21 in promoting humoral recall responses and in sustaining autoimmune inflammation.
26102289We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting.
26108174IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection.
26108174Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity.
26108174Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells.
26108174IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling.
26108174Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression.
26108174Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T-cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo.
26129991The cytokines IFN-γ, IL-4, IL-17, IL-21, IL-22, and TGF-β were measured by enzyme-linked immunosorbent assay.
26129991Higher expressions of serum IFN-γ, IL-17, IL-21, and IL-22 were observed in CHC patients than in HCs, but the differences were not significantly different in CHC patients and HCV-related MC patients.
26138292The enforced Bcl-3 expression increased, but Bcl-3 silencing decreased, the numbers of IL-21-producing Tfh-like cells.
26138292CONCLUSION: Bcl-3 is involved in the development of Tfh cells and the pathogenesis of RA, presumably by inducing IL-21 production.
26152611In PsA SF samples, IL-2, IL-21 and IFN-γ were not detectable, whereas IL-6 and IL-1β levels were higher than in SF of non-inflammatory osteoarthritis patients.
26156866Downstream of IL-23, CD21L expression was significantly associated with IL-17F, IL-21, and IL-22, but not IL-17A in two independent ST sample sets.
26158513Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition.
26158513These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program.
26158860CpG oligodeoxynucleotides (ODNs) upregulate the interleukin-21 receptor (IL21R) and enhance IL-21-mediated cytotoxicity in chronic lymphocytic leukemia (CLL) B cells.
26158860We demonstrate that treatment of CLL B cells with the ODN CpG-685 leads to increased IL21R expression, and that this increased expression enhances the effects of IL-21 treatment as evidenced by increased phosphorylation of JAK1, STAT1, and STAT3, as compared to IL-21 treatment without prior CpG stimulation.
26158860Induction of IL21R by CpG-685 also enhanced IL-21-mediated cytotoxicity.
26158860Here, we demonstrate that luciferase reporter constructs containing the Sp1 binding site have increased basal luciferase activity compared to constructs lacking the Sp1 binding site, but fail to increase luciferase activity with CpG-685 stimulation in CLL B cells.
26158860These findings suggest an alternative mechanism for induction of IL-21 receptor in CLL B cells and provide a basis for creation of future combination therapies.
26171402We recently described processing of mouse lung epithelial IL-22 receptor (IL-22R) by ubiquitination on the intracellular C-terminal.
26171402To identify cellular factors that regulate human IL-22R, we screened receptor abundance while overexpressing constituents of the ubiquitin system and identify that IL-22R can be shuttled for degradation by multiple previously uncharacterized F-box protein E3 ligase subunits.
26171402FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro.
26171402FBXW12 knockdown with shRNA increases IL-22R abundance and STAT3 phosphorylation in response to IL-22 cytokine treatment.
26171402These findings indicate that the heretofore-undescribed protein FBXW12 functions as an E3 ligase constituent to ubiquitinate and degrade IL-22R and that therapeutic FBXW12 inhibition may enhance IL-22 signaling and bolster mucosal host defense and infection containment.
26202426Amyotrophic lateral sclerosis (ALS) is caused by selective loss of upper and lower motor neurons by complex mechanisms that are incompletely understood.
26202426Next, we review evidence from ALS patients and transgenic mutant SOD1 mice for weight loss, hypermetabolism, hyperlipidemia and mitochondrial dysfunction in disease onset and progression.
26202426We also present evidence that additional ALS-linked proteins, TDP-43 and FUS, lead to energy disruption and mitochondrial defects in motor neurons.
26202426Lastly, we review emerging evidence including our own that dysregulation of the AMPK signalling cascade in motor neurons is an early and common event in ALS pathogenesis.
26233805Sardinian multiple sclerosis population: the TARDBP Ala382Thr mutation and C9orf72 expansion.
26233805Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.
26233805Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background.
26233805Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion.
26233805TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population.
26234378The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology.
26234378The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations.
26235375SUBJECTS AND METHODS: The serum concentrations of IL-17, IL-21, IL-22, IL-6, and TNF-α were measured in 47 patients with AA and 40 healthy controls.
26235375RESULTS: The serum concentrations of IL-17, IL-21, IL-22, IL-6, and TNF-α were significantly higher in patients with AA as compared with healthy controls (mean: IL-17 33.
26235375IL-21 62.
26238370Aqueous humor and sera were collected and the concentration of 15 immune mediators (IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, TNF-α, IFN-γ, sCD40L) were measured in both aqueous humor and sera simultaneously by multiplex immunoassay.
26250498We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.
26250498Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2.
26261240Moreover, SUMOylation-deficient WASp favors ectopic development of the TH17-like phenotype (↑IL17A, IL21, IL22, IL23R, RORC, and CSF2) under TH1-skewing conditions, suggesting a role for WASp in modulating TH1/TH17 plasticity.
26264610Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons associated with the abnormal aggregation of ubiquitinated proteins.
26264610The molecular mechanisms underlying the pathogenesis of ALS remain unclear, however.
26264610Defects at various stages of autophagy have been associated with pathological mutations of several ALS-linked genes including SOD1, p62, TDP-43, and optineurin, suggesting that such defects may play a causative role in the pathogenesis of this condition.
26264610In this review, we summarize the dysregulation of autophagy associated with ALS as well as potential therapeutic strategies based on modulation of the autophagic process.
26269257IL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells.
26269257Here we show that IL-21 unexpectedly induces IL-1β production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-κB-independent pathway.
26269257IL-21 does not induce Il1b expression in CD4(+) T cells, with differential histone marks present in these cells versus cDCs.
26269257Moreover, STAT3-dependent IL-1β expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with pneumonia virus of mice.
26269257These results demonstrate lineage-restricted IL-21-induced IL-1β via a non-canonical pathway and provide evidence for its importance in vivo.
26281250OBJECTIVE: This study aimed to detect the immunoexpression of interleukin-21 (IL-21) and receptor activator.
26281250The interaction of IL-21 with RANKL and its role in periapical pathogenesis were also speculated.
26281250All tissues were subjected to immunohistocheincal analysis with anti-human IL-21 and RANKL polyclonal antibodies.
26281250The correlations of IL-21 with RANKL, lesion size, and the occurrence of tenderness of the PGs and RCs were evaluated.
26281250RESULTS: IL-21-positive cells were detected in all periapical lesion tissues but not in normal tissues.
26281250In the cyst group and granuloma group, the corresponding expression levels of IL-21 were 59.
26281250Moreover, t-test revealed a significantly higher expression of IL-21 and RANKL in RCs than in PGs (P<0.
26281250IL-21 and RANKL were positively correlated in both PGs and RCs (P<0.
26281250Furthermore, IL-21 was correlated with lesion size (P<0.
26281250CONCLUSION: This study demonstrated that IL-21 is potentially involved in the pathogenesis of apical periodontitis lesions.
26281250Further studies are required to elucidate the specific functions of IL-21 in periradicular inflammatory processes.
26303227Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death.
26303227E322K missense mutation in exon 10 of OPTN in one familial ALS patient who additionally had a C9ORF72 mutation.
26303227We conclude that: (i) OPTN mutations are associated with ALS; (ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS; (iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient; and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration.
26313265The WF harvested from patients underwent NAC showed significant higher profiles of interleukin-1β (IL-1β), IL-4, IL-6, IL-17F, IL-21, IL-23, IL-25, IL-31, Interferon γ (IFNγ), CD40 ligand (CD40L), tumor necrosis factor α (TNFα), CXCL1, CXCL2, CXCL5, CCL3, CCL7 and CCL20.
26320059Anticancer Cytokines: Biology and Clinical Effects of Interferon-α2, Interleukin (IL)-2, IL-15, IL-21, and IL-12.
26320059Here, we review the basic biology and the clinical experiences with IFN-α, IL-2, IL-15, IL-21, and IL-12.
26320128The aim of this study was to determine whether endogenous factors [B cell activating factor (BAFF) and IL-21] and exogenous factors [oligodeoxynucleotides containing CpG motifs (CpG-ODN)] synergize in stimulating PR3-ANCA production in GPA patients.
26320128METHODS: Peripheral blood mononuclear cells from GPA patients and healthy controls (HCs) were cultured in the presence of BAFF and IL-21, with or without CpG-ODN, for 12 days.
26320128Phenotypic characterization and the influence of CpG-ODN treatment on IL-21 receptor (IL-21R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and BAFF receptor (BAFF-R) expression on B cells was analysed by flow cytometry.
26320128Mechanistically, CpG-ODN up-regulated IL-21R and TACI expression on B cells, possibly sensitizing these cells for IL-21- and BAFF-mediated signals.
26320128Agents inhibiting Toll-like receptor 9, BAFF and IL-21 signalling pathways may serve as potential therapeutics for intervention in GPA patients.
26345892Association between IL-21 polymorphism and systemic lupus erythematosus: a meta-analysis.
26345892Several case-control studies have been conducted to investigate the association between Interleukin-21 (IL-21) polymorphisms and systemic lupus erythematosus (SLE) susceptibility, and most of the studies focused on IL-21 rs907715 and rs2221903 polymorphisms.
26345892For the IL-21 rs907715 polymorphism, seven sets of comparisons involving 7977 SLE cases and 8097 healthy controls were considered.
26345892Results showed that there were significant differences in the IL-21 rs907715 genotype distribution between SLE patients and healthy controls in the comparisons of all genetic models.
26345892For the IL-21 rs2221903 polymorphism, seven sets of comparisons involving 7990 SLE cases and 8098 healthy controls were considered.
26345892This meta-analysis suggests that the both IL-21 rs907715 and rs2221903 polymorphisms may be associated with SLE susceptibility.
26345892As current evidence remains limited, further studies are needed to warrant the association between IL-21 rs907715 and rs2221903 polymorphisms and SLE susceptibility.
26351408IL-17A, IL-22, IL-6, and IL-21 Serum Levels in Plaque-Type Psoriasis in Brazilian Patients.
26352837IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured.
26352837Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients.
26353115Plasma levels of interleukin (IL)-6, IL-17 and IL-21 were measured by immunoassay, radiographs of hands and feet were examined and disease activity score (DAS28) was determined.
26362943De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients.
26362943In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases.
26362943There are only few reports on de novo FUS mutations in juvenile ALS patients.
26362943To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted.
26362943Here, we screened a cohort of 14 early-onset sporadic ALS patients (onset age <35 years) to determine the frequency of mutations in C9orf72, SOD1, and FUS in this defined patient cohort.
26362943No mutations were detected in SOD1 or C9orf72; however, we identified 6 individuals (43%) carrying a heterozygous FUS mutation including 1 mutation that has not been described earlier (c.
26362943Genetic testing of FUS thus seems indicated in sporadic early-onset ALS patients especially if showing predominant bulbar symptoms and an aggressive disease course.
26379855IL-21 does not involve in OVA-induced airway remodeling and chronic airway inflammation.
26379855Interleukin (IL-21) is a member of the type I cytokine family with sequence homology to IL-2, IL-4, and IL-15.
26379855IL-21 has been reported to improve symptoms of allergic rhinitis in mice.
26379855In this study we examined whether IL-21 signaling involved in allergic airway inflammation and remodeling in vivo by using ovalbumin (OVA)-induced chronic asthma model.
26379855Moreover, expression of IL-13 and TGF-β was not affect by intranasal administration with recombinant mouse IL-21 or anti-IL-21R antibody.
26379855These results indicated that IL-21 signaling might not play an important role in airway inflammation and remodeling.
26413871IL-17-producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial.
26413871Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals.
26413871Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21-mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity.
26415324Janus kinase 1 and 3 (JAKI and JAK3), blocking interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
26429540METHODS: We detected the percentages of CD4⁺CXCR5⁺, CD4⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺ T cells in peripheral blood mononuclear cells (PBMCs) by flow cytometry, the level of Bcl-6 mRNA in CD4⁺ T cells by reverse transcription PCR, and the level of interleukin 21 (IL-21) in plasma by ELISA in healthy controls and asthma patients during acute exacerbation and post-treatment release periods.
26429540The linear regression analysis was used to analyze the correlations of the level of IL-21 in plasma with forced expiratory volume in one second/forced vital capacity (FEV1/FVC) and forced expiratory volume in one second/prediction (FEV1/Pre) in acute exacerbation period of asthma patients.
26429540RESULTS: The percentages of CD4⁺CXCR5⁺, CD4⁺CXCR5⁺ICOS⁺ T cells in PBMCs, the level of Bcl-6 mRNA in CD4⁺T cells, and the level of IL-21 in plasma increased in acute exacerbation of the asthma patients compared to the healthy controls.
26429540After treatment, the percentages of CD4⁺CXCR5⁺, CD4⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺ T cells in PBMCs, the level of Bcl-6 mRNA in CD4⁺T cells, and the level of IL-21 in plasma in asthma patients were all reduced as compared with the acute exacerbation period.
26429540There were negative correlations between IL-21 and lung function parameters such as FEV1/FVC and FEV1/Pre.
26456588The serum levels of anti-dsDNA antibody, anti-nuclear antibody, IL-21, and IL-10 were detected using ELISA kits.
26456588Furthermore, prednisone treatment decreased serum IL-21 and IL-10 levels and reduced the expression of splenic Blimp-1 and Bcl-6 (two key regulatory factors for plasma cell differentiation) in MRL/lpr mice.
26456588CONCLUSION: Prednisone treatment restricts B lymphocyte differentiation into plasma cells in MRL/lpr mice, which may be correlated with the inhibition of IL-21 production and the restoration of the balance between Blimp-1 and Bcl-6.
26466984Biological effects of IL-21 on different immune cells and its role in autoimmune diseases.
26466984Interleukin-21 (IL-21) is a member of the common γ-chain cytokines with broad pleiotropic actions that affects different immune and nonimmune cells.
26466984IL-21 can affect differentiation, proliferation and function of T and B cells; it can also induce the maturation and enhance the cytotoxicity of CD8+ T cells and Natural killer (NK) cells.
26466984IL-21 exerts major effects on B-cell activation and differentiation or apoptosis during humoral immune responses and induces differentiation of naïve B cells and memory B cells into plasma cells.
26466984IL-21 also affects different subtypes of T cells including T helper-17 (TH17), T follicular helper (TFH) and regulatory T (Treg) cells and thereby promotes the development of autoimmune disorders and inflammatory diseases.
26466984Observations have shown that the blockade of IL-21 has therapeutic effects on various autoimmune diseases in animal models.
26466984IL-21 in the context of each specific autoimmune disease or tissue-specific pathological microenvironments will be helpful in developing novel treatments to control autoimmune diseases.
26466984Herein, we review the biological effects of IL-21 on different immune cells and uncover the emerging role of this interesting cytokine in autoimmune diseases.
26472479High production of IL-6, IL-17 and IL-21 by CD4(+) T-cells was detected in NMO patients.
26472479Further, IL-21 and IL-6 levels were related directly to the level of neurological disabilities.
26472479The addition of anti-IL-6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL-6, IL-17 and IL-21 release by CD4(+) T cells.
26482544To evaluate whether interleukin-21 (IL-21) could promote proliferation and proinflammatory cytokine production by RA-FLS, immunohistochemistry and immunoblotting were performed to observe the expression of IL-21 receptor (IL-21R) in synovial tissues and FLS from RA and osteoarthritis (OA) patients.
26482544The signalling pathways triggered by IL-21 were characterized by immunoblotting.
26482544Fc attenuated IL-21-induced proliferation and secretion of TNF-α and IL-6.
26482544Moreover, IL-21 induced activation of the ERK1/2, PI3K/AKT and STAT3 pathways, and blockade of these pathways attenuated IL-21-induced proliferation and secretion of TNF-α and IL-6.
26482544These results suggest that IL-21 could promote RA-FLS proliferation and production of proinflammatory cytokines.
26490738F4(+) ETEC infection upregulated IL-17A, IL-17F, IL-21 and IL-23p19, but not IL-12 and IFN-γ mRNA expression in the systemic and mucosal immune system.
26491200IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses.
26491200In addition to cell surface-expressed molecules, cytokines produced by Tfh cells, such as IL-21 and IL-4, provide B cell helper signals.
26491200IL-21 also influenced responsiveness to IL-4 because expression of both membrane IL-4R and the IL-4-neutralizing soluble (s)IL-4R were reduced in Il21r(-/-) mice.
26491200Taken together, these findings underscore the important collaboration between IL-4 and IL-21 in shaping T-dependent Ab responses.
26500105Furthermore, PBMC from MG patients were purified and stimulated with LPS (TLR4 agonist) with or without transfection of TIPE2 expressing adenovirus, then the expression of TIPE2 and Th17-specific transcriptional factor RORγt and the IL-6, IL-17 and IL-21 levels of supernatant were analized.
26500105Furthermore, TIPE2 mRNA presents a significantly negative correlation with the serum levels of IL-6, IL-17 and IL-21 in either generalized patients or ocular patients.
26500105In cultured MG PBMC, TLR4 activation led to the down-regulation of TIPE2, while the expression of RORγt and production of IL-6, IL-17 and IL-21 were significantly increased.
26514432From transcriptomic to protein level changes in TDP-43 and FUS loss-of-function cell models.
26514432The full definition of the physiological RNA targets regulated by TDP-43 and FUS RNA-binding proteins (RBPs) represents an important issue in understanding the pathogenic mechanisms associated to these two proteins in amyotrophic lateral sclerosis and frontotemporal dementia.
26514432In this study by using the Affymetrix Exon Arrays, we were able to assess and compare the effects of both TDP-43 and FUS loss-of-function on the whole transcriptome using the same human neuronal SK-N-BE cell model.
26514432We showed that TDP-43 and FUS depletion induces splicing and gene expression changes mainly distinct for the two RBPs, although they may regulate common pathways, including neuron differentiation and cytoskeleton organization as evidenced by functional annotation analysis.
26514432Contrarily to a loss-of-function mechanism, we showed that mutant TDP-43 proteins maintained their splicing activity in human ALS fibroblasts and experimental cell lines.
26517519Circulating Tfh cells in HCC patients were defective in the production of IL-21 in vitro, which was in accordance with lower IL-21 levels in tumor tissues than in para-tumor tissues.
26537567We have taken advantage of an IL-22 expressing adeno-associated virus (AAV-IL-22) to address the potential role of IL-22 in not only protecting mice from autoimmune cholangitis, but also in treating animals with established portal inflammation.
26551680Compared with SIV-infected animals only given ART, SIV-infected RMs given both ART and IL-21 showed improved restoration of intestinal Th17 and Th22 cells and a more effective reduction of immune activation in blood and intestinal mucosa, with the latter maintained through 8 months after ART interruption.
26551680At the latest experimental time points, which were up to 8 months after ART interruption, plasma viremia and cell-associated SIV DNA levels remained substantially lower than those before ART initiation in IL-21-treated animals but not in controls.
26551680Together, these data suggest that IL-21 supplementation of ART reduces residual inflammation and virus persistence in a relevant model of lentiviral disease and warrants further investigation as a potential intervention for HIV infection.
26559315Second, only the numbers of CD4CXCR5ICOSPD1 Tfh cells correlated with the Epstein-Barr virus (EBV) DNA load, negatively correlated with the numbers of naive B cells and amount of IL-21, and positively correlated with the numbers of plasma cells, memory B cells, and atypical lymphocytes.
26559812Furthermore, IL-17A, IL-21, IL-22, and IL-23 are all demonstrated to be directly mitogenic to human colorectal cancer cell lines.
26605911Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules.
26605911BACKGROUND: Amyotrophic lateral sclerosis (ALS), a debilitating neurodegenerative disorder of the motor neurons, leads to the disorganization of the neurofilament (NF) cytoskeleton and - ultimately - the deterioration of the neuromuscular junction.
26605911Some familial cases of ALS are caused by mutated FUS, TDP-43 or SOD1; it is thought that the mutated proteins inflict pathology either by gain or loss of function.
26605911Whether sAPP, FUS, TDP-43 and SOD1 are mechanistically linked in a common pathway deregulated in both AD and ALS is not known.
26605911SUMMARY: We show that sAPP, TDP-43, FUS and SOD1 are transported to neurite terminals by a mechanism that involves endoplasmic reticulum (ER)-like tubules and requires peripherin NFs.
26605911Knocking down peripherin disrupts the NF network and diminishes the accumulation of sAPP, TDP-43, FUS, SOD1 and Rtn4 at terminals.
26635528ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad.
26635528Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood.
26635528Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients.
26635528Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable.
26635528Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described.
26646950Moreover, IL-21 induced activation of the phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription-3 (STAT-3) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT-3 inhibitor STA-21 and ERK1/2 inhibitor PD98059] attenuated IL-21-induced migration and secretion of MMP-3 and MMP-9.
26648777MATERIAL AND METHODS: We examined the expression of IL-21, IL-17 and IFN-γ in UC patients and controls by enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
26648777RESULTS: We found that IL-21 was expressed on CD3(+)CD8(-)T cells by flow cytometry.
26648777Plasma IL-21 level and the percentage of CD3(+)CD8(-)IL-21(+) T cells were significantly elevated in UC patients compared to controls.
26648777Moreover, we found a significant positive correlation between CD3(+)CD8(-)IL-21(+)T cells and Th17 cells.
26669444Various agents that raise intracellular cAMP and activate PKA (activators of adenylate cyclase or inhibitors of phosphodiesterase 4) promoted degradation of short-lived (but not long-lived) cell proteins generally, model UPS substrates having different degrons, and aggregation-prone proteins associated with major neurodegenerative diseases, including mutant FUS (Fused in sarcoma), SOD1 (superoxide dismutase 1), TDP43 (TAR DNA-binding protein 43), and tau.
26692931Cancer stem cell vaccine expressing ESAT-6-gpi and IL-21 inhibits melanoma growth and metastases.
26692931The results demonstrated that the B16F10-ESAT-6-gpi/IL-21 CD133(+)CD44(+) CSC vaccine exhibited enhanced anti-melanoma efficacy as determined by inhibited melanoma growth, prolonged survival of melanoma bearing mice.
26692931Thus, the B16F10-ESAT-6-gpi/IL-21 CD133(+)CD44(+) CSC vaccine may be used to reactivate the anti-tumor immunity and for treatment of melanoma.
26709668The distribution of TLOs, T cells, follicular dendritic cells, B cells, and follicular regulatory T (Tfr) cells, as well as Ki67, peripheral lymph node addressin (PNAd), podoplanin, AID, IL-17, IL-21, IL-10, and C4d expression were detected by immunohistochemistry.
26709668Correlations between lymphoid neogenesis and the expression of IL-17, IL-21, C4d, podoplanin, IL-10, and Foxp3 were evaluated.
26720885The objective of this study was to produce an optimized form of IL-21 with improved stability.
26720885Plasmids encoding the murine IL-21 alone (pIL-21) or IL-21 genetically fused to portions from mouse IgG3 (pIL-21/Ig) were constructed, and the efficiency of expression, protein kinetics, biodisponibility, and function were analyzed.
26720885The genetic constructions of pIL-21 and pIL-21/Ig were transfected into HEK 293 cells, and significant levels of functional IL-21 were obtained.
26720885The amino acid of murine IL-21 and IgG3 cloned showed 100% identity with correspondent published sequences.
26720885At 24 h of incubation, increased levels of IL-21 were detected in the supernatants of pIL-21.
26720885At 72 h of culture, the levels of IL-21 in the supernatant of cells transfected with pIL-21/Ig were significantly higher than those secreted by pIL-21-transfected cells.
26720885Furthermore, the data showed that our chimeric IL-21/Ig present improved systemic disponibility in BALB/c mice and conserved the intrinsic ability to increase the frequency of CD4(+) T cells, NKT cells, and CD8(+) T cells.
26725561Although it has been shown that the differentiation of in-vitro Th17 cells culture conditions requires the presence of IL-1beta, IL-23, IL-2, IL-21, IL-6 and TGF-β, the optimum amount of TGF-β regulating in vitro human Th17 cell differentiation is still unclear.
26748727Since its discovery in 2000, interleukin-21 (IL-21) has been shown to display a broad spectrum of pleiotropic actions including the regulation of development, differentiation and function of lymphoid-myeloid cells.
26748727More specifically, IL-21 modulates the effector functions of T, B and NK cells, which not only have key roles in antitumoral and antiviral immunity but also in exerting major effects on inflammatory responses promoting the development of autoimmune diseases.
26748727Recent studies have unveiled an unexpected role for IL-21 in immune regulation and de novo T-cell development.
26748727While highlighting its critical role in immunity, this review will mainly focus on recent advances in IL-21 biology and how such newly discovered properties could potentially be exploited therapeutically in the establishment of future clinical trials.
26751167The molecular machinery responsible for cytosolic accumulation of misfolded TDP-43 in amyotrophic lateral sclerosis (ALS) remains elusive.
26751167Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation.
26751167Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center.
26751860Molecular basis of ALS and FTD: implications for translational studies.
26751860Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival.
26751860For ALS, there is only a drug Riluzole and a promising substance arimoclomol.
26751860The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels.
26751860Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date.
26751860The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes.
26751860TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis.
26751860The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins.
26751860Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins.
26755203RESULTS: In vitro, there was a significant reduction of the Th17 cytokines interleukin (IL)-17 and IL-21.
26756888Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment.
26756888Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains.
26756888We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers.
26756888Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model.
26757760METHODS: Expressions of IL-21 and IL-22 were examined immunohistochemically in 36 patients with KD and 7 normal controls.
26757760RESULTS: The IA of IL-21 [M(Q): 1 373 418 (1 800 926)] and IL-22 [M(Q): 462 086(484 672)] in KD was significantly higher than those in normal controls [M(Q): 70 445(44 658), 51 599(71 241), P < 0.
26757760The overexpression of IL-21 was significantly associated with pruritus (Z = -1.
26757760Moreover, IL-21 was identified for disease recurrence (Z = -2.
26757760There was no association between IL-21, IL-22 and age, gender, laterality, maximum size.
26772733Therefore, in this study, we investigated the ability of Th-17 regulatory cytokines, specifically IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis.
26772733METHODS: Primary human fibroblasts, ASM cells, and lung endothelial cells line were treated with IL-21, IL-22, and IL-23 cytokines before incubation with dexamethasone and the level of apoptosis was determined by measuring cellular Annexin-V using Flow cytometry.
26772733Interestingly, inhibiting STAT3 phosphorylation abrogated IL-21, IL-22, and IL-23 anti-apoptotic effect on fibroblasts and endothelial cells.
26776123The study reported here investigated the level of mRNA expression of different cytokines: Tumour necrosis factor-alpha (TNF-α), interferon (INF)-gamma, interleukin-10 (IL-10) and IL-21 in the peripheral blood mononuclear cell among the antiretroviral therapy naive subtype C HIV-1 infected individuals and normal healthy controls by real time polymerase chain reaction.
26776123IL-21 showed a positive correlation with CD4 counts (r=0.
26776123There was a significant negative correlation between the cytomegalovirus (CMV) viral load and IL-21 expression.
26776472LD3ED III-immunized mice enhance wide ranges of T cell responses as indicated by IFN-γ, IL-17, IL-21 production.
26795249We assessed circulating HIV-specific IL-21(+)CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells.
26795249Together, we identify IL-21(+)CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.
26804609Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS in various populations remains unclear.
26804609The aim of this study was to determine the frequency and spectrum of mutations in TBK1 in a Taiwanese ALS cohort of Han Chinese origin.
26804609Among them, the genetic diagnoses of 168 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, and TUBA4A had been excluded.
26804609ALS-frontotemporal dementia.
26804609The frequency of TBK1 mutations in ALS patients in Taiwan is, therefore, approximately 0.
26810447The serum cytokines interleukin (IL)-17, IL-6, IL-21, interferon (IFN)-γ, and IL-4 levels were determined with enzyme-linked immunosorbent assay method.
26810447IL-21, IFN-γ, and IL-4 levels showed no obvious difference.
26812299METHODS: The levels of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40L and TNF-α were measured in cerebrospinal fluid (CSF) and plasma in subjects with MS (n=15), NPH (n=18) and controls (n=11) by multiplex assay.
26812299RESULTS: The increased levels of IL-1β, IL-6, IL-10, IL-21 and TNF-α in cerebrospinal fluid of NPH subjects in comparison with MS patients and controls were found.
26812299CONCLUSION: The enlarged brain ventricles in NPH may repress and activate brain structures to the production of IL-1β, IL-6, IL-10, IL-21 and TNF-α, reflecting the inflammatory basis in NPH affected brain.
26833462Dose-dependent total IL-21 (free IL-21 and IL-21‒NNC0114-0005 complexes) accumulation was observed.
26833462Accumulation of IL-21-containing complexes suggests neutralization of the target cytokine.
26833462Based< on this trial, further trials to explore the efficacy of anti-IL-21 were initiated.
26840345At baseline, IL-21, triglyceride (TG), cholesterol (CHOL), glutanyltransferase (GGT), body mass index (BMI), and computed tomography (CT) ratio of liver/spleen showed significant difference between the 2 groups.
26840345Only the level of IL-21 exhibited significant increase from 0 to 12 weeks, while the change line of other associated factors was nearly parallel between EVR group and non-EVR group.
26840345We deduced that IL-21 was associated with EVR, and the elevated level of IL-21 at treatment week 12 can predict EVR in CHB + NAFLD patients.
26849077Tumor samples from 17 pancreatic cancer specimens were cultured with cytokines (IL-2, IL-15, and IL-21) to expand TILs.
26878294Th17 cells are characterized as preferential producer of interleukins including IL-17A, IL-17F, IL-21 and IL-22.
26882474IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22.
26882474The production of IL-17 and IL-21 by IRF4 can be augmented by its phosphorylation by the serine-threonine kinase ROCK2.
26883061The p110α/δ inhibitor ETP-46321, or p110α plus p110δ inhibitors also inhibited IL-21 secretion by differentiated CD4(+) T follicular (Tfh) or IL-17-producing (Th17) helper cells.
26884645Increased IL-21 Expression Induces Granzyme B in Peripheral CD5(+) B Cells as a Potential Counter-Regulatory Effect in Primary Sjögren's Syndrome.
26884645We investigated the expression of intracellular GrB and IL-21 receptor (IL-21R) of CD19(+)CD5(+) and CD19(+)CD5(-) B cells; furthermore, we determined the IL-21 expression of iNKT cells as well.
26884645CD5(+) but not CD5(-) B cells showed elevated GrB and IL-21R expression in pSS; additionally IL-21 expression of iNKT cells was also elevated.
26884645Our results suggest that enhanced IL-21R expression of CD19(+)CD5(+) B cells and production of IL-21 by iNKT cells may play an important role in the pathogenesis of pSS by regulating CD19(+)CD5(+) B cell functions and increasing GrB production, presumably leading to a counter-regulatory effect in the disease.
26884958IL-17A, IL-17F, IL-21, IL-22 or IL-23 could not be detected.
26891767Less common gene mutations, such as those in TARDBP, CHMP2B, VCP, FUS and TREM2, can also present as atypical parkinsonism.
26915990For identification of target RNAs recognized by TDP-43, we purified TDP-43 in soluble dimer form and subjected to in vitro systematic evolution of ligands by exponential enrichment (SELEX) screening.
26915990Two lines of evidence indicated that loss of function of TDP-43 results in the neurodegenerative disorder: (i) amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43M337V lacks the activity of binding and transport of G4-containing mRNAs; and (ii) RNA containing G4-forming GGGGCC repeat expansion from the ALS-linked C9orf72 gene absorbs TDP-43, thereby reducing the intracellular pool of functional TDP-43.
26915990Taken together, we propose that TDP-43 within neurons plays an essential role of mRNA transport into distal neurites for local translation, and thus, dysfunctions of TDP-43 cause neural diseases such as ALS and frontotemporal lobar degeneration.
26919046Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients.
26919046The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls.
26919046ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting.
26919046Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines.
26919046Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected.
26919046However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some.
26923014CONCLUSION: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.
26927371After 7-day treatment, compared with the model group, the levels of IL-6, IL- 17, IL-21 and TNF-α in the sera of the fluconazole group, 15.
26934574In the present study we investigated the serum cytokine profile (IL-17, IL-23, IL-21, IL-4, IL-12), representing cellular and humoral immunity and assessed the level of VZV IgG antibodies in patients with herpes zoster.
26934574METHODS: We investigated the serum concentrations of IL-17, IL-23, IL-21, IL-4, IL-12 and the level of VZV IgG antibodies in 23 patients with herpes zoster who did not develop superinfection.
26934574RESULTS: In patients with herpes zoster, the serum level of IL-17, IL-23, IL-21, IL-4 and IL-12 as well as VZV IgG antibodies titer were statistically significantly increased compared to control group.
26942409Here we demonstrate that calves infected with BRSV express significant levels of IL-17, IL-21 and IL-22; and both CD4 T cells and γδ T cells contribute to this response.
26942409IL-17, IL-21 and IL-22.
26945006Rapid expansion of mTCRβ(+) T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, interleukin-2 (IL-2), IL-15, and IL-21 resulted in a preponderance of effector (CD27(-)CD45RA(-)) and less-differentiated (CD27(+)CD45RA(+)) T cells.
26945832Based on the available studies on the role of IL-21 associated with several cells, including T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells as well as regulatory B cells and regulatory T cells, the possible roles of this cytokine in pemphigus were discussed in detail.
26945832It was found that IL-21 is a crucial cytokine associated with pemphigus disease, which has not been discussed in this disease yet.
26945832By inhibition of IL-21 or its receptor, it is expected that patients with severe pemphigus experience relative and gradual improvement.
26945832This inhibition could be induced by tofacitinib, which was approved by the US Food and Drug Administration as a treatment for rheumatoid arthritis patients, or anti-IL-21 monoclonal antibody, NNC114-0006.
26954363We found that Th17 cells and Th17-related cytokines, such as IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23 and TGF-β, are not only directly involved in the pathogenesis but also collaborated with B cells and B cell-related antibody production to induce CNS lesions.
26971227The expression of IFN-γ, IL-12p70, IL-5, IL-13, IL-17F, IL-22, IL-23, TGF-β1, IL-10 and IL-21 associated with Th1, Th2, Th17, regulatory T cells (Treg) and TFH cells were analyzed using a Quantibody array.
26971227The expressions of cytokines associated with the CD4(+) Th lineage were higher in CHC patients than in HCs, except for IL-21.
26972116Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin.
26972116Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age.
26972116Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear.
26972116We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients.
26972116Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified.
26972116Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin.
26972116Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course.
26983850Rho-associated kinase 2 (ROCK2) recently was shown to be implicated in regulation of interleukin-21 (IL-21) and IL-17 secretion in mice and humans.
26983850The therapeutic potential of targeted ROCK2 inhibition in the clinic was solidified further by human data demonstrating the KD025 inhibits the secretion of IL-21, IL-17, and interferon γ along with decreasing phosphorylated STAT3 and reduced protein expression of interferon regulatory factor 4 and B-cell lymphoma 6 (BCL6) in human peripheral blood mononuclear cells purified from active cGVHD patients.
26984187Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects.
26984187Importantly, these findings were replicated in two other amyotrophic lateral sclerosis mouse models based on TDP-43 (Tardbp) and FUS mutations.
26987909Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum.
27016280The identification of a hexanucleotide repeat expansion in a non-coding region of C9orf72 as a major cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) drastically changed the field of research on both of these conditions.
27016280The hexanucleotide repeat expansion forms RNA foci in the central nervous system (CNS) of repeat-positive FTD and ALS patients, and these foci are believed to sequester RNA-binding proteins (RBPs) and impair their function in RNA processing.
27016280Finally, the hexanucleotide repeat also induces the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) through an as yet unknown mechanism.
27016280This review covers the different potential pathogenic factors that have been put forth for C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS), while highlighting some remaining questions.
27018846The productions of interleukin (IL) IL-1β, IL-2, IL-6, IL-10, IL-17, IL-21, IL-23 and transforming growth factor beta 1 (TGF-β1) were assessed.
27029896Expression of PC1 was greatly increased in B cells stimulated with the combination of CD40 ligand, interleukin (IL)-4 and IL-21.
27056076The aim of this study was to obtain the mutation prevalence of CHCHD10 and the phenotypes with mutations in Chinese ALS patients.
27056076ALS patients including 487 sporadic ALS (SALS) and 12 familial ALS (FALS), from the Department of Neurology, West China Hospital of Sichuan University, were screened for mutations of all exons of the CHCHD10 gene by Sanger sequencing.
27056076All patients identified with mutations of CHCHD10 gene were screened for mutations of the common ALS causative genes including C9orf72, SOD1, TARDBP, FUS, PFN1, and SQSTM1.
27056076No mutation was found in the aforementioned common ALS causative genes in the patients who carried CHCHD10 mutations.
27056076Chinese SALS population suggests CHCHD10 gene mutation appears to be an uncommon cause of ALS in Chinese populations.
27062692Interleukin-21 (IL-21), which belongs to IL-2 γ chain receptor cytokine family, is as an important regulator of immune responses.
27062692In this study, we developed a novel strategy for immunizing mice with a DNA/vaccinia/protein vaccine in the presence or absence of mouse IL-21 (mIL-21) to evaluate whether mIL-21 could enhance immune responses.
27064076Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that targets motor neurons in the brain, brainstem and spinal cord.
27064076Several proteins misfold and are associated either genetically or pathologically in ALS, including superoxide dismutase 1 (SOD1), Tar DNA binding protein-43 (TDP-43), Ubiquilin-2, p62, VCP, and dipeptide repeat proteins produced by unconventional repeat associated non-ATG translation of the repeat expansion in C9ORF72.
27064076In this review we provide an overview of the current literature regarding the molecular mechanisms of protein misfolding and aggregation in ALS, and the role of chaperones as potential targets for therapeutic intervention.
27071061HPAI H5N1 virus induced excessive expression of type I IFNs (IFNA and IFNG), cytokines (IL1B, IL18, IL22, IL13, and IL12B), chemokines (CCL4, CCL19, CCL10, and CX3CL1) and IFN stimulated genes (OASL, MX1, RSAD2, IFITM5, IFIT5, GBP 1, and EIF2AK) in lung tissues.
27087014Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology.
27087014On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma.
27087014Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on nucleocytoplasmic transport dysfunction as a mechanism leading to disease pathophysiology.
27118610OBJECTIVE: Interleukin-21 (IL-21) is a cytokine that is an important modulator of immune responses.
27118610Here, we investigated the expression and distribution of IL-21 in a kainic acid (KA)-induced acute seizure mouse model.
27118610IL-21 mRNA and protein expression levels were measured using RT-PCR and western blotting.
27118610Immunohistochemistry and immunofluorescence staining were performed to further characterize the pattern and distribution of IL-21 expression.
27118610RESULTS: The IL-21 mRNA and protein expression levels in the hippocampal tissues of the KA-treated mice were significantly increased as early as 1 h compared with the age-matched mice and PBS-treated mice.
27118610Immunohistochemical staining showed that IL-21 expression was distributed throughout the hippocampus, including areas CA1 and CA3, the dentate gyrus and the hilus.
27118610Moreover, immunofluorescence further showed that in the hippocampi of the KA-treated mice, IL-21 was mainly expressed in GFAP-positive astrocytes rather than in NeuN-positive neurons or CD11b-positive microglia.
27118610SIGNIFICANCE: Our data suggest that an increase in astrocyte-derived IL-21 expression in hippocampal subregions following KA-induced seizures may have potent regulatory effects on epileptogenesis.
27122304Interleukin-21 (IL-21), as a multifunctional cytokine, plays an important role in many diseases, such as cancer, inflammatory and autoimmune diseases.
27122304We aimed to investigate the relationship between polymorphisms of IL-21 gene and susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in a Chinese population.
27122304Genomic DNA was isolated from peripheral blood, and the polymerase chain reaction-ligase detection reaction (PCR-LDR) method was used to genotype the SNPs (rs2221903, rs907715 and rs12508721) within IL-21 gene.
27122304Our results showed that IL-21 polymorphisms were associated with the risk of HCC and chronic HBV infection when compared with healthy controls.
27122304Our findings suggest that the rs12508721T/C and rs2221903A/G polymorphisms of IL-21 gene are associated with the susceptibility of HBV-related HCC and chronic HBV infection.
27122304However, the function in these SNPs of IL-21 gene needs to clarify the mechanisms involved in the pathogenesis of HBV-related HCC further.
27133050Reinforcing B16F10/GPI-IL-21 vaccine efficacy against melanoma by injecting mice with shZEB1 plasmid or miR200c agomir.
27133050In this study, we hypothesized that the inhibition of epithelial to mesenchymal transition (EMT) program by knockdown of Zinc-finger E-box binding homeobox 1 (ZEB1) or administration of miR200c agomir would strengthen the B16F10 cells transfected with GPI-anchored IL-21 (B16F10/GPI-IL-21) vaccine efficacy in inhibiting the melanoma metastasis.
27133050Our findings from the current study indicated that, when compared with the mice immunized with the B16F10/GPI-IL-21 vaccine alone, the mice immunized with B16F10/GPI-IL-21 vaccine combined with injection of shZEB1 plasmid or miR200c agomir not only meaningfully inhibited EMT of melanoma, reduced the EMT characteristic molecular expression in tumor tissues, but also significantly decreased the Treg cells and TGF-β1, enhanced the cytotoxicities of NK cells and cytotoxic T lymphocytes and the IFN-γ level.
27133050Our study demonstrated that using the B16F10/GPI-IL-21 vaccine in combination with the down-regulated ZEB1 or miR200c administration effectively elicited anti-tumor immunity and reduced melanoma metastasis by inhibiting the EMT program in the B16F10 melanoma-bearing mice.
27141361TNFα production by BDCA-1+ DC and non-classical monocytes in response to Type-I IFN, (ii) a strong drop in IFNγ production by NK cells in response to either Type-I IFN or TLR7/8 ligand, and (iii) a coordinated impairment of cytokine (IL-2, IFNγ, IL-21) production by T cell subpopulations.
27152115In addition, an increase in IL-17 and IL-21 serum levels following therapy was observed in both groups of patients.
27152115On the other hand, increased levels of IL-21 (an inducer of Th17 cells) and of IL-17 may be interpreted as a protective mechanism, which likely leads to neutrophil recruitment in cURTI patients.
27156907To examine whether Tim-3(+) identifies exhausted Tfh cells, we stimulated Tfh cells with anti-CD3/CD28, and found that Tim-3(+) T cells expressed reduced frequencies of chemokine CXCL13 and cytokine interleukin 21 (IL-21), and contained fewer proliferating cells, than Tim-3(-) Tfh cells.
27166223In addition, we take resent findings for nucleocytoplasmic transport defects of TDP-43, as discussed for hexanucleotide repeat expansions in C9orf72 into account and provide a hypothesis how the interplay of altered nuclear transport and protein degradation leads to the accumulation of protein deposits.
27176825Furthermore, increased levels of Th17-related cytokines including IL-17, IL-21, IL-23, IL-1β, and IL-6 were presented in between blood and marrow in B-ALL patients.
27176825Both IL-17A and IL-21, two Th17-secreted cytokines, induced the proliferation of B-ALL cell line Nalm-6 and patient B-ALL cells isolated from B-ALL patients, herein either cytokine led to the phosphorylation of Akt and Stat3.
27178390AIMS: Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases.
27178390We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation.
27178390Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes.
27178390CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups.
27178390Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72.
27178390In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes.
27178390Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.
27178567Multiple regression analysis, however, found that joint expression of IL-17A, IL-17F, IL-21, RORC, and TGF-β was significantly predictive of REI (P < 0.
27198976IL-17A, IL-17F, IL-21, IL-22, IFN-γ, IL-10, IL-9 and IL-6 were significantly associated with AF risk independently of potential confounders.
27198976IL-17A, IL-21, IL-10 and IL-6 levels were positively correlated with left atrial diameter; IL-17F level was negatively correlated with left ventricle ejection fraction among AF patients (P < 0.
27224005IL-13)] and T helper type 17 (IL-17, IL-21, IL-22, IL-23) splenic T-cell cytokine responses.
27233967IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner.
27233967In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44.
27233967More importantly, IL-21-propagated HLA-DR(+) NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4(+) T cell priming inducing the differentiation of uncommitted central memory T cells.
27233967Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4(+) T cell interactions promoting a specific expansion of central memory lymphocytes.
27266984Moreover, the levels of IL-21 in serum and the expression of IL-21 mRNA were higher in acute schistosomiasis patients.
27283128Th17-related cytokines in mucositis: is there any difference between peri-implantitis and periodontitis patients?OBJECTIVE: This study aimed to compare Th17-related cytokines named IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, sCD40L and TNF-α in peri-implant fluid (PIF) from mucositis sites in patients having either peri-implantitis, periodontitis or without interproximal alveolar bone loss.
27283128In group 2, IL-21 level was significantly higher in mucositis compared to peri-implantitis sites (P = 0.
27303608Therefore, this study compares the serum concentrations of IL-21, IL-17, and transforming growth factor β (TGF-β) between patients with major depressive disorder and healthy controls.
27303608However, the level of IL-21 was not statistically different between the two groups 84.
27306193IL-21 has pleiotropic effects on both myeloid and lymphoid immune cells and as a consequence, the biological actions of IL-21 are broad: regulating both innate and adaptive immune responses and playing a pivotal role in antiviral, inflammatory and antitumour cellular responses.
27306193While IL-21 genes have been characterized in mammals, birds, fish and amphibians, there are no reports for any marsupial species to date.
27306193The open reading frame of macropod IL-21 is 462 nucleotides in length and encodes a 153-mer putative protein that has 46% identity with human IL-21.
27306193Despite the somewhat low amino acid conservation with other mammals, structural elements and residues essential for IL-21 conformation and receptor association were conserved in the macropod IL-21 predicted peptides.
27306193The detection of IL-21 gene expression in T-cell-enriched tissues, combined with analysis of the promotor region of the tammar wallaby gene, suggests that macropod IL-21 is expressed in stimulated T cells but is not readily detected in other cells and tissues.
27306193The similarity of gene expression profile and functionally important amino acid residues to eutherian IL-21 makes it unlikely that the differences in B- and T-cell responses that are reported for some marsupial species are due to a lack of important functional residues or IL-21 gene expression in this group of mammals.
27320894Nine HBV transgenic mice were injected subcutaneously with recombinant mouse interferon alpha (rmIFN-α) and another 9 transgenic mice were injected with PBS, and their HBsAg, HBV DNA, IL-6, and IL-21 levels and frequencies of peripheral blood CD4(+)T and CD19(+)B cells were detected.
27320894RESULTS: HBV transgenic mice showed a high level of HBsAg with a detectable level of HBcAb and significantly increased serum levels of IL-21 and IL-6 as compared with WT mice (P<0.
27321923Remarkably, HIPK2 activation positively correlates with TDP-43 proteinopathy in NEFH-tTA/tetO-hTDP-43ΔNLS mice, sporadic ALS and C9ORF72 ALS, and blocking HIPK2 kinase activity protects motor neurons from TDP-43 cytotoxicity.
27329723IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells.
27330746Interleukin-21 (IL-21) and its receptor (IL-21R) are broadly expressed on human B cells, activated T cells and other myeloid cells.
27330746IL-21 cooperates with IL-6 and transforming growth factor-β to regulate T-cell differentiation.
27330746IL-21-mediated human B cell and dendritic cells differentiation requires signal transducer and activator of transcription 3 (STAT3), and also induces B-cell apoptosis dependents on the Toll-like receptor signal.
27330746Recently, in vitro and in vivo experiments showed that IL-21/IL-21R regulate angiogenesis through STAT3.
27330746IL-21 signaling pathways are complex due to its cooperation with other transcriptional factors, such as interferon regulatory factor 4 and granulocyte-macrophage colony-stimulating factor.
27330746With the increase in the understanding of IL-21 biology in the context of each specific disease or pathological condition, IL-21 could be a new therapeutic target for immune-related disease.
27369896Myotubes derived from patients carrying the C9orf72 repeat expansion show no change in differentiation efficiency and normal TDP-43 localization after as many as 120 days in vitro when compared to unaffected controls.
27400126Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume.
27400126The gene encoding the IL-21 receptor (Il21r) showed a marked difference in strain-specific transcription levels and coding variants in neonatal and adult cortical tissue.
27400126In brain slice explants, oxygen deprivation (OD) activated apoptotic pathways and increased neuronal cell death in IL-21 receptor-deficient (IL-21R-deficient) mice compared with control animals.
27400686Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults.
27400686Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis.
27400686Approximately 10 % of ALS patients have familial form of the disease.
27400686Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others.
27400686Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens.
27400686In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease.
27400686For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models.
27400686Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.
27405876Interleukin-21 (IL-21), a member of IL-2 cytokine family, has pleotropic biological effects on lymphoid and myeloid cells.
27405876During the past 15 years, since the discovery of IL-21, great advances have been made regarding its biological activity and the mechanisms controlling IL-21-mediated cellular responses, especially in hematological malignancies.
27405876Preclinical studies have shown that IL-21R is expressed on healthy and neoplastic B-cells and exogenous IL-21 can induce direct apoptosis of IL-21R expressing B-cell non-Hodgkin lymphomas (NHL), making it a potentially attractive anti-lymphoma therapy.
27405876However, in some hematological malignancies such as multiple myeloma, Hodgkin lymphoma and Burkitt lymphoma, IL-21 can induce proliferation of neoplastic B-cells.
27405876Immunomodulatory effects of IL-21 have also been reported to contribute to its anti-tumor effects as described by earlier studies in solid tumors and B-cell associated malignancies.
27405876These effects are predominantly mediated by IL-21's ability to activate cytolytic activities by NK-cells and CD4+/CD8+ T-cells.
27405876In this review, we provide an overview of IL-21's effects in NHL, results from clinical trials utilizing IL-21, and propose how IL-21 can be therapeutically exploited for treating these lymphomas.
27409425In this study, CART cells targeting folate receptor-alpha were generated and expanded ex vivo in the presence of different cytokines (IL-2, IL-7, IL-15, IL-18, and IL-21), and their expansion, phenotype and cytotoxic capacity were evaluated, in vitro and in vivo.
27409425IL-7 induced the highest proportion of memory stem cell-like CART cells in the final product, and IL-21 supported the expansion of CART cells with a younger phenotype, while IL-2 induced more differentiated CART cells.
27409425In contrast, the administration of IL-15 and IL-21 in combination with CART cells in vivo increased their tumor killing capacity.
27409425According to our results, IL-7 and IL-15 show promise to promote ex vivo expansion of CART cells, while IL-15 and IL-21 seem better suited for in vivo administration after CART cell infusion.
27429419Compared with age-matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL-21 levels in serum.
27429419IFNγ inhibited, whereas IL-21 promoted, B cell IL-10 competence in vitro.
27429419B10 cell frequencies and numbers were decreased in children with autoimmunity, which may be explained in part by alterations in serum IFNγ and IL-21 that differentially regulate B10 cell development.
27435400IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells.
27435400We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status.
27435400The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer.
27435400RESULTS: NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment.
27435400In response to cetuximab-coated pancreatic tumor cells, IL-21-treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1.
27435400CONCLUSIONS: These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy.
27447555The frequency of HBV-specific CD4+CXCR5+ T cells and the production of IL-21 by intrahepatic CD4+CXCR5+ T cells of mice with acute HBV infection were increased after stimulation.
27447555Furthermore, the expression of function-related molecules of intrahepatic CD4+CXCR5+ T, including Bcl-6, CXCR5, IL-6, IL-6R, IL-21 and IL-4 in the liver was increased during acute HBV infection.
27478614The DEGs were first annotated, and results revealed that the expression of inflammation-related genes, including IL-1β, IL-2, IL-22, CCL19, CCL8, CX3CR1, CXCL6, INHBE, LEPR, PRL, and TNFRSF9 found in the cytokine-cytokine receptor pathway were up-regulated in the HC-fed cows, indicating local inflammation in the rumen epithelium was triggered.
27491077Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43(A315T) mice.
27491077Similar to our recent results in SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased 5' adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression.
27498357Tfh) and IL-21 have emerged as central players in this process.
27500457Further, Sp1 was identified as a downstream transcription factor, and the inhibition of p38 MAP kinase and Sp1 with their inhibitors led to the abrogation of bendamustine-induced IL-10 production and the DNA binding of Sp1.
27500457Importantly, when PBMC from healthy donors were cultured with bendamustine at the concentration of 30μM, under the stimulation with an anti-IgM antibody, an anti-CD40 antibody, recombinant human IL-21 (rhIL-21) and recombinant human soluble BAFF (rhsBAFF), IL-10 production by B cells (CD20+CD4-CD8-CD14-) among peripheral blood mononuclear cell (PBMC) was significantly enhanced by adding bendamustine.
27535236In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice.
27535236CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset.
27535236CONCLUSION: IL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.
27543298The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy.
27543298In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) mutations, as well as Alzheimer's disease and hippocampal sclerosis.
27551984IL-22 promoted CD3+ T cell infiltration by IL-22R induced STAT3 phosphorylation in murine acute graft versus host disease target organs after allogeneic bone marrow transplantation.
27551984Furthermore, the increased expression of IL-22R and its downstream protein P-STAT3 were detected in GVHD mice with IL-22 treated.
27551984These results suggested that the pathological role of IL-22 in GVHD target organs contribute to exogenous injected IL-22 as well as secreted IL-22 from the infiltrated allo-reactive effector T cells.
27573866They initially localized proximally to mutating B cells, secreted interleukin 21 (IL-21), induced expression of the transcription factor Bcl-6 and selected high-affinity B cell clones.
27573866As the GC response evolved, TFH cells extinguished IL-21 production and switched to IL-4 production, showed robust expression of the co-stimulatory molecule CD40L, and promoted the development of antibody-secreting B cells via upregulation of the transcription factor Blimp-1.
27599586Interleukin-21 (IL-21) promotes osteoclastogenesis in RA in a receptor activator of nuclear factor-κB ligand (RANKL)-dependent way.
27599586Whether IL-21 is capable of promoting osteoclastogenesis directly in the absence of RANKL remains unknown.
27599586In the present study, we examined the osteoclastogenic activity of IL-21 in RAW264.
27599586We found that IL-21 enhanced osteoclastogenesis and this was demonstrated by increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive stained, multinucleated cells compared with the negative control.
27599586Western blot analysis and immunocytochemistry showed the positive expression of calcitonin receptor (CTR) in the IL-21 group.
27599586RT-PCR and RT-qPCR also verified the increased mRNA expression of CTR and cathepsin K in the IL-21 group compared with the negative control.
27599586The scanning electronic microscope images showed a few resorption pits on the bone slices cultured with IL-21.
27599586The phosphoinositide 3-kinase (PI3K)/AKT pathway inhibitor LY294002 significantly suppressed IL-21-induced osteoclastogenesis.
27599586IL-21 may promote osteoclastogenesis through the PI3K/AKT signaling pathway.
27603722PURPOSE: The purpose of this study was to determine levels of the cytokines IL-1β, IL-6, IL-21, IL-22, and IL-23 and the chemokines CXCL13, CCL19, CCL20, and CCL21 in aqueous humor (AH) samples from patients with specific uveitic entities.
27603722RESULTS: Cytokines IL-1β, IL-21, IL-22, and IL-23 were not detected in any AH sample.
27611173OBJECTIVES: Therefore, the aim of this case control study was to determine the serum level of IL-17, IL-21, IL-27, transforming growth factor beta (TGF-β), and IFN-γ and their reciprocal relationship in Iranian T1D patients.
27611173RESULTS: The serum levels of IL-17 and IL-21 were significantly higher in T1D patients compared to the healthy individuals (p = 0.
27665947Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected.
27665947Downregulation of CXCR4 by IL-21 was intact.
27665947In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro.
27671790When expressed from C3H or B6 alleles, ARNTL2 inhibits the transcription of interleukin 21 (Il21), a major player in the regulation of immune responses.
27671790IL-21 injection abolishes the B6 allele-mediated decrease of apoptosis and proliferation.
27671790Interestingly, IL-21 also leads to an increase in thymic proinflammatory Th17 helper cells.
27671790Our results identify Arntl2 as a gene controlling thymocyte apoptosis and proliferation along with Th17 development through the IL-21 pathway.
27688759Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism.
27688759Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death.
27688759Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods.
27688759All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture.
27688759In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions.
27688759Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible.
27697141Follicular T helper cells and IL-21 in rheumatic diseases.
27697141Interleukin 21 (IL-21) is thought to exert key functions in controlling and directing the T and B cell responses leading to formation of antibodies and autoantibodies alike.
27697141IL-21 is a signaling molecule secreted by a subpopulation of T cells called follicular T helper (Tfh) cells.
27697141The first part of this study addresses whether plasma levels of IL-21 influence disease activity in rheumatic disease.
27697141We further investigate the distribution of IL-21-producing Tfh cells in these patients.
27697141We find that IL-21 plasma levels correlate to disease activity and radiological progression in RA, and that the IL-21-producing Tfh cell are increased in the blood and synovial fluid of these patients.
27697141These findings support the idea that IL-21 and Tfh cells are linked to the development and perpetuation of these diseases.
27697141We find that microRNA-155 can regulate IL-21's capacity to signal, while microRNA-21 is important for survival of T cells.
27716404In the present study, we performed a comprehensive analysis to clarify the clinicopathological characteristics of patients with amyotrophic lateral sclerosis (ALS) that had progressed to result in a totally locked-in state (communication Stage V), in which all voluntary movements are lost and communication is impossible.
27716404The time from ALS onset to the need for tracheostomy invasive ventilation was less than 24 months in ten patients.
27721128Furthermore, ∆F/TriAdj induced higher gene expression of activation-induced cytidine deaminase (AID), as well as IL-6, IL-21, TGF-β cytokines, which are key players in IgA class switch recombination, ultimately leading to a sustained long-term memory response.
27725866IL-1β, IL-6, IL-21 and/or TNF-a promoted Th22 cells differentiation from CD4+ T cells.
27729219We also discuss the serum levels of Th17, Treg related cytokines including IL-17, IL-21, IL-22, IL-10, analyzing correlation between ITK and Th17/Treg related cytokines.
27729219CD4+pITK+ T cells were related to levels of IL-17, IL-21.
27768524In a recent study, we investigated this possibility by reducing expression of C9orf72 in cell lines and primary neurons and found that C9orf72 regulates the initiation of autophagy.
27769184The frequencies of these six subpopulations and the circulating level of Tfh-related cytokine interleukin 21 (IL-21) were measured from 27 patients with IgAV and 15 healthy controls (HC) by flow cytometry and flow cytometric bead array, respectively.
27769184When the disease entered the remission stage following treatment, circulating levels of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high and CXCR5+CD45RA-IL-21+ Tfh cells, as well as plasma IL-21 levels were reduced.
27769184Among the six subpopulations of Tfh cells, both CD4+CXCR5+ICOS+ and CXCR5+CD45RA-IL-21+ significantly and positively correlated with serum IgA and plasma IL-21 levels, but only CXCR5+CD45RA-IL-21+ significantly and negatively correlated with the serum C4 level.
27769811Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected.
27769811Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection.
27769811In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis.
27769811Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1.
27774526The Inflammatory Cytokine IL-21 is Expressed by Splenic Neutrophils in Response to Transplantation of Allogeneic Cells.
27774526Intracellular IL-21 was demonstrated in the allogeneic neutrophils on day 7 before and after in vitro stimulation.
27774526In conclusion Purified neutrophils isolated from the spleen on day 7, the early peak of allogeneic transplantation a GVHD, express high levels of IL-21 message and intracellular IL-21.
27774606The interleukin (IL)-21/IL-21 receptor (R) is a promising system to be exploited for the development of therapeutic strategies.
27774606Although the biological activities of IL-21 and its cell signalling events have been largely studied in immunocytes, its interaction with human monocytes and macrophages have been neglected.
27774606Previously, we reported that IL-21 enhances Fc gamma receptor (FcRγ)-mediated phagocytosis in human monocytes and in human monocyte-derived macrophages (HMDM) and identified Syk as a novel molecular target of IL-21.
27774606Here, we elucidate further how IL-21 promotes phagocytosis in these cells.
27774606Unlike its ability to enhance phagocytosis of opsonized sheep red blood cells (SRBCs), IL-21 did not promote phagocytosis of Escherichia coli and zymosan by monocytes and did not alter the cell surface expression of CD16, CD32 and CD64.
27774606In HMDM, IL-21 was found to enhance phagocytosis of zymosan.
27774606Using a pharmacological approach, we demonstrate that IL-21 enhances phagocytosis by activating some mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)-Akt and Janus kinase (JAK)-STAT pathways.
27774606These results obtained in human monocytes and macrophages have to be considered for a better exploitation of the IL-21/IL-21R system for therapeutic purposes.
27813377Eotaxin, FGF, Fraktalkine, GCSF, GMCSF, Granzyme A, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-21, IP-10, I-TAC, MCP-1, MIG, MIP-1α, MIP-1β, RANTES, TNF-α, and VEGF) in each 50 μL of blood and seminal plasma during the andrological work-up.
27819158Blood samples were taken from 125 ALS patients, including nine patients with C9orf72 or SOD1 mutation, at regular intervals of six months.
27819158Results showed that, at baseline, serum concentrations of NF-L but not PGRN or S100B discriminated significantly between ALS and controls.
27819158In conclusion, serum NF-L in any ALS disease stage is a promising marker to support diagnosis and predict outcome, while serum PGRN and S100B are only of minor prognostic value.
27820809By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged.
27838743Five structurally and functionally different proteins, an enzyme superoxide dismutase 1 (SOD1), a TAR-DNA binding protein-43 (TDP-43), an RNA-binding protein FUS, a cofilin-binding protein C9orf72, and polypeptides generated as a result of its intronic hexanucleotide expansions, and to lesser degree actin-binding profilin-1 (PFN1), are considered to be the major drivers of amyotrophic lateral sclerosis.
27838743To this end, we employed a broad set of computational tools for intrinsic disorder analysis and conducted intensive literature search to gain information on the structural peculiarities of SOD1, TDP-43, FUS, C9orf72, and PFN1 and their intrinsic disorder predispositions, and the roles of intrinsic disorder in their normal and pathological functions.
27865860METHODS: Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFH cells.
27865860RESULTS: B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing TFH cell maturation.
27878721In vitro production of immunoregulatory cytokines (IFN-α, IL-31, TNF-β, IL-17A, IL-7, IL-1RA, IL-1α, IL-10, IL-15, IL-21, IL-22, IL-23, IL-27, and IL-9) by dendritic cell cultures was compared in ski athletes and healthy donors.
27878721In both groups, dendritic cells did not secrete IL-15, IL-21, IL-22, IL-23, IL-27, and IL-9.
27895726In the present study, adenovirus-mediated interleukin 21 (Ad5-IL-21-EGFP) gene expression was induced in Hepa1-6 cells to investigate whether IL-21 was capable of enhancing antitumor immunity and reducing tumorigenicity of Hepa1-6 in a mouse model.
27895726Mice were inoculated intradermally into the right flank with Hepa1-6 cells or Hepa1-6 cells infected with Ad5 or Ad5-IL-21.
27895726The levels of IL-21, IL-4 and interferon (IFN)-γ levels in mouse serum and tumor tissues were detected by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry.
27895726The expression of IL-21 was confirmed by reverse transcription-polymerase chain reaction, western blot analysis and ELISA assay in Ad5-IL-21-EGFP-infected Hepa1-6 cells.
27895726The overexpression of IL-21 significantly reduced the tumorigenicity of Hepa1-6 cells.
27895726The tumor volumes and tumor weights in Ad5-IL-21-Hepa1-6 mice were much smaller than those in the Ad5-Hepa1-6 group and Hepa1-6 wild-type group.
27895726The immunohistochemistry and ELISA assay demonstrated that IL-21 and IFN-γ levels were much higher while the IL-4 level was much lower in the Ad5-IL-21-Hepa1-6 group than in the other two groups.
27895726CCK-8 assay revealed that the killing ability of NK cells and T cells, and the proliferation ability of T cells in Ad5-IL-21-Hepa1-6 mice were higher than in the other two groups; the spleen index of Ad5-IL-21-Hepa1-6 mice was also higher than in the other groups.
27895726In conclusion, IL-21 reduces tumorigenicity of Hepa1-6 by a mechanism involving enhanced activation of cell-mediated immunity in tumor-bearing mice.
27902338Recombinant rabies virus expressing IL-21 enhances immunogenicity through activation of T follicular helper cells and germinal centre B cells.
27902338Previous studies have demonstrated that the lack of interleukin-21 (IL-21) signalling could affect specific antibody induction after rabies vaccination.
27902338Here, to further investigate the over-expression of IL-21 on the immunogenicity of rabies virus (RABV), a recombinant RABV expressing murine IL-21, designated LBNSE-IL21, was constructed and evaluated in a mouse model.
27924822IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis.
27924822NKp46+CD27+KLRG1+ NK cells expanded in healthy individuals with latent TB infection in an IL-21-dependent manner.
27924822Our study provides first evidence that memory-like NK cells survive long term, expansion depends on IL-21, and involved in vaccine-induced protective immunity against a bacterial pathogen.
27930290The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known.
27930290In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles.
27957331METHODS: Luciferase immunoprecipitation (LIPS) was used to screen for autoantibodies to IL-6, IL-1β, TGF-β3, IL-21, and IL-23 in patients with APECED or thymoma.
27965670When IL-1RI gene expression was silenced using siRNA, human naive CD4+ T cells cultured in the presence of Th17-polarizing cytokines had a significantly decreased expression of interleukin regulatory factor 4 (IRF4), RORc, IL-17A, IL-17F, IL-21, IL-22, and IL-23R genes, confirming that IL-1RI signaling induces Th17 cell differentiation.
27987496The transcript levels of B-cell lymphoma 6 (Bcl-6), as well as IL-21 and IL-21R, were measured by real-time polymerase chain reaction.
27987496Besides, serum IL-21 and CXCL13 concentrations were determined by enzyme-linked immunosorbent assay.
27987496IL-21 mRAN[0.
27987496Additionally, the serum interleukin-21 (IL-21) and CXCL13 levels in the RA patients were higher than in the healthy controls [IL-21, (200.
28027499In addition, an imbalance between pro- and anti-inflammatory pathways has been proposed to play an important role in the pathogenesis of several neurodevelopmental disorders including autism; however, the role of anti-inflammatory molecules IL-27 and CTLA-4 and pro-inflammatory cytokines IL-21 and IL-22 has not previously been explored in autistic children.
28027499In the current study, we investigated the expression of IL-21, IL-22, IL-27, and CD152 (CTLA-4) following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically-developing children (TD) with phorbol-12-myristate 13-acetate (PMA) and ionomycin.
28027499In our study, cells from children with AU had increased IL-21 and IL-22 and decreased CTLA-4 expression on CD4+ T cells as compared with cells from the TD control.
28043029CD4+IL-21+T cells are correlated with regulatory T cells and IL-21 promotes regulatory T cells survival during HIV infection.
28043029INTRODUCTION: IL-21 enhances T and natural killer cells survival and antiviral functions without promoting T cell activation during HIV infection, which makes it a better adjuvant in anti-HIV immunotherapy.
28043029Due to the pleiotropy and redundancy of cytokines, it is vital to have a comprehensive knowledge of the role of IL-21 in the regulation of immune responses.
28043029In this study, we explored the direct effect of IL-21 on Tregs during HIV infection, which has not been addressed before.
28043029METHODS: Thirty-four HIV treatment-naïve patients were enrolled and the relationship between CD4+IL-21+T cells and Tregs were studied.
28043029The effects of IL-21 on CD4+CD25+CD127low Tregs' apoptosis, proliferation, and CTLA-4 and TGF-β expression in HIV-infected patients was investigated and compared with the effect of other common γ-chain cytokines.
28043029RESULTS: We found the percentage and absolute numbers of CD4+IL-21+T cells were positively related to the frequency or absolute numbers of CD4+CD25+ or CD4+CD25+CD127low Tregs.
28043029Compared with the media-alone control, IL-21, IL-7, and IL-15 could significantly reduce apoptosis of Tregs (p<0.
28043029IL-21 did not promote the proliferation of Tregs as compared with media alone, while IL-2, IL-7, and IL-15 could significantly increase the proliferation of Tregs (p<0.
28043029IL-21 enhanced CTLA-4 expression by Tregs (p<0.
28043029There were no significant differences of the fold induction of apoptosis, proliferation, or CTLA-4 and TGF-β expression by Tregs from HIV-infected patients and normal controls after IL-21 treatment.
28043029In vitro experiment showed that pretreatment with IL-21 significantly enhanced the suppressive effect of Tregs on CD8+ T cells' IFN-γ expression.
28043029CONCLUSION: We conclude that IL-21 promotes the survival and CTLA-4 expression of Tregs and enhanced the suppressive capacity of Tregs during HIV infection.
28050571How Does Interleukin-22 Mediate Liver Regeneration and Prevent Injury and Fibrosis?Interleukin-22 (IL-22) is a pluripotent T cell-derived cytokine which is a member of IL-10 cytokine family.
28050571IL-22BP is an inhibitor of IL-22 which has 20-1000x more affinity to bind with IL-22 compared to IL-22R1 that inhibits IL-22 activity.
28072389Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106.
28072389Expanded GGGGCC repeats in the first intron of the C9orf72 gene represent the most common cause of familial amyotrophic lateral sclerosis (ALS), but the mechanisms underlying repeat-induced disease remain incompletely resolved.
28093521OSM mitigated the proliferation of Th17 cells and decreased the expression of IL-17 and IL-21.
28108473METHODS: Immunohistochemical analysis of IL-21 and pERK1/2 was performed in 18 cases of KD and five gender- and age-matched control samples.
28108473In comparison with gender- and age-matched controls, patients showed strong in situ expressions of IL-21 and pERK1/2, respectively (p<0.
28108473Patients with strong IL-21 staining intensity and overexpression of pERK1/2 had a lower recurrence rate than those with moderate staining intensity (p=0.
28108473IL-21 were not.
28124082Compared with the age-matched healthy control, the level of IL-17 was higher and the levels of IFN-γ, IL-4, and IL-21 were lower.
28137826We observed substantially enhanced IL-21R-mediated signaling by the fusokine compared with native IL-21 at equimolar concentrations.
28137826Fusokine treatment led to direct apoptosis of lymphoma cell lines and primary tumors that otherwise were resistant to native IL-21 treatment.
28137826In addition to direct cytotoxicity, the fusokine enhanced NK cell activation, effector functions, and interferon γ production, resulting in greater antibody-dependent cell-mediated cytotoxicity compared with IL-21 and/or anti-CD20 antibody treatments.
28137826Further, the αCD20-IL-21 fusokine stabilizes IL-21 and prolongs its half-life.
28137826In vivo αCD20-IL-21 therapy resulted in a significant tumor control in the rituximab-resistant A20-huCD20 tumors.
28140446When compared with the control group, CHC patients showed a lower proportion of IL-17-secreting (CD4+ and CD8+ ) T cells capable of simultaneously producing IL-21.
28140446Notably, advanced liver lesions were observed among those patients with lower percentage levels of IL-17-producing T cells positive for IL-21, interferon-γ (IFN-γ) and IL-10.
28140446The percentage of IL-17+ IL-21- IFN-γ+ (CD4+ and CD8+ ) T-cell phenotypes was positively associated with plasma CD14 levels.
28141856We demonstrated previously that mixed expression of macrophage-activating (IFN-γ) and regulatory (IL-4, IL-10, IL-21) cytokines, parasite-induced expression of macrophage arginase 1 (Arg1), and decreased production of nitric oxide are key immunopathologic factors.
28146052We sought to determine whether the substitution or addition of IL-21 to culture had a similar effect.
28146052DLN lymphocytes were antigen-sensitized with 4T1 mammary carcinoma 10 days prior to harvest, activated with B/I, and expanded in culture for 7 days with either IL-2, IL-21, IL-2/21, IL-7/15, or IL-7/15/21.
28146052We found that T cells grown in IL7/15/21 demonstrated significantly greater lymphocyte expansion than IL-2, IL-21, IL-2/21, and IL-7/15 (38.
28146052TCM) compared to IL-2, IL-21 and IL-2/21 (45.
28146052IL-21 and IL-2/21-expanded T cells preferentially differentiated into T naïve cells (TN) vs.
28146052In vivo adoptive immunotherapy (AIT) experiments demonstrated anti-tumor efficacy was equally effective using IL-2, IL-21, IL-2/21, IL-7/15 and IL-7/15/21-cultured lymphocytes vs.
28148298TBK1: a new player in ALS linking autophagy and neuroinflammation.
28148298Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure.
28148298Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport.
28148298Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1.
28148298TBK1 is required for efficient cargo recruitment in autophagy; mutations in TBK1 may result in impaired autophagy and contribute to the accumulation of protein aggregates and ALS pathology.
28149833Up-regulation of humoral genes IL-7 and IL-21 were also noted.
28157399After PMA+ionomycin stimulation, CXCR5+ CD8+ T cells from CHB patients presented significantly higher transcription level of interferon gamma (IFN-γ), interleukin 10 (IL-10), and IL-21, as well as higher IL-10 and IL-21 protein secretion, than CXCR5- CD8+ T cells.
28189042Cytokine expression (IL-1β, IL-4, IL-6, IL-10, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IL-17A, IL-17F, IFN-γ, sCD40L, and TNF-α) was evaluated using bead-based multiplex technology.
28189042IL-4, IL-10 and IL-21 expressions were significantly increased in gingival tissue from patients with an active disease as compared to those with a disease in remission.
28189042The inflammation score (mean value of IL-1β, IL-6, IL-21, and sCD40L) was significantly higher in gingival tissue from patients with IBD activity.
28197386Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis.
28197386IL-21 has reported activity in promoting both Th1 and Th17 immune responses.
28197386We aimed to delineate the role of IL-21 in a model of sporadic intestinal carcinogenesis.
28197386We found that in APCMIN/+ mice, ablation of IL-21 increased intestinal tumorigenesis.
28197386Expression of pro-inflammatory Th17-associated genes, including RORγt and IL-17A, was increased in the intestine in the absence of IL-21, while expression of antitumor Th1-associated genes Tbet, IFNγ, granzyme B, and perforin was decreased.
28197386Similarly, the IL-21-deficient APCMIN/+ mouse intestines had fewer infiltrating T cells as well as decreased effector memory T cells, NK cells, and granzyme B-expressing cells.
28197386Finally, our data suggest that IL-21 impairs Th17 immune responses as mesenteric lymph nodes from IL-21-deficient mice had increased IL-17A expression, and naive helper T cells from IL-21-deficient mice were more prone to differentiate into IL-17A-secreting cells.
28233079IL-21 Is Positively Associated with Intervertebral Disc Degeneration by Interaction with TNF-α Through the JAK-STAT Signaling Pathway.
28233079This study was conducted in order to investigate the function of IL-21 in intervertebral disc degeneration.
28233079Immunohistochemistry and western blot analysis were performed to detect the expression of IL-21, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-7), and tumor necrosis factor alpha (TNF-α) in degenerated intervertebral disc (IVD) tissues of human and rat.
28233079Moreover, nucleus pulposus (NP) cells were treated with 0, 10, 100, and 1000 ng/mL of IL-21 cytokine with and without AG490.
28233079IL-21, ADAMTS-7, and TNF-α can be detected in the degenerative NP tissues in both human and rat degenerated NP tissues.
28233079The mRNA expression of ADAMTS-7, TNF-α, and MMP-13 was enhanced after stimulation with IL-21.
28233079Compared to control, STAT-1, STAT-3, and STAT-5b expression was also enhanced after IL-21 treatment, with STAT-3 being the most significantly enhanced; furthermore, expression was significantly reduced after treatment with AG490.
28233079The mRNA expression of TNF-α was markedly reduced after treatment with AG490 compared to treatment with IL-21 only.
28233079IL-21 is involved in the pathological development of IVD degeneration and IL-21 could aggravate IVD degeneration by stimulating TNF-α through the STAT signaling pathway.
28239749IL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression.
28239749FOXP3 expression was most potently induced by tumours secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation.
28239749We conclude that Treg induction in naïve T cells is a common phenomenon amongst a number of different cancers and that the ability of IL-21 to counteract this effect is further evidence of its promise in cancer therapy.
28243360Vice versa, IL-21 concentrations were detected only in H people but they were undetectable in the Ob counterpart.
28243360In addition, polyphenols were able to significantly increase levels of H IL-21, while this was not the case in Ob people.
28243360Since IL-21 is an inducer of Th17 cells, it is likely that polyphenols may suppress the sources of this cytokine via production of IL-10.
28259000The levels of IL-21 were increased in the CSHB group and were positively correlated with AST, TB and DB in patients with chronic HBV infection.
28259000CONCLUSIONS: Th17/Treg imbalance and increased IL-21 are associated with liver injury in patients with chronic HBV infection.
28263097Tfh-cell differentiation is regulated by the coordinated functions of distinct cytokines, including interleukin (IL)-6, IL-21, IL-12, IL-23, IL-2, IL-7 and transforming growth factor-β (TGF-β), as well as transcription factors, including B-cell lymphoma 6 protein (Bcl-6), Signal transducers and activators of transcription (STAT)1, STAT3, STAT4, B-cell activating transcription factor (Batf), interferon regulatory factor 4 (IRF4), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (C-Maf), T-cell-specific transcription factor 1 (TCF-1) and Achaete-scute homolog 2 (Acl2), which have been shown to form a complex transcriptional network.
28314758Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis.
28344074Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients.
28344074Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease.
28344074In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients.
28344074Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons.
28344074The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention.
28346226BLyS) engenders survival and antibody secretion, whereas CD40 costimulation with IL-21 or IFN-γ promotes a T-bet+ B cell phenotype.
28358365Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells.
28378248Interleukin-21 (IL-21) enhances the survival and cytotoxic properties of cytotoxic T cells (CTLs) and exhibits essential roles in controlling chronic viral infections.
28378248The mean mRNA expression of IL-21 in the non-activated and activated PBMCs was higher (by 5-13 times) in the HAM/TSP patients than in ACs and HCs (p < 0.
28378248In contrast to the IL-21 mRNA expression, the serum level of the IL-21 protein was significantly lower in the HAM/TSP patients than in ACs and HCs (p < 0.
28378248IL-21 gene expression (R = 0.
28378248In conclusion, the increase in IL-21 mRNA expression may reflect the attempt of infected T cells to induce an appropriate antiviral response, and the decrease in IL-21 protein expression may reflect the inhibition of IL-21 mRNA translation by viral factors in favour of virus evasion and dissemination.
28405022Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset.
28405022There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia.
28405022Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression.
28405022However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed.
28405022Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2.
28405022First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice.
28405022Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.
28413901Elevation of CD16+CD56+ NK-cells and down-regulation of serum interleukin-21 (IL-21) and IL-1α after splenectomy in relapsed hemophagocytic lymphohistiocytosis of unknown cause.
28413901We also examined seven patients for the changes in cytokine levels before and after splenectomy and found that IL-21 and IL-1α decreased at 4 wk after splenectomy (P < 0.
28413901The mechanism is likely related to the changes in percent NK cells and cytokines (IL-21 and IL-1α) after surgery.
28427414Observational study of Interleukin-21 (IL-21) does not distinguish Kawasaki disease from other causes of fever in children.
28427414The aim of this study is to assess the validity of IL-21 as a diagnostic biomarker for KD in febrile children in North America.
28427414IL-21 levels were measured using commercial ELISA kits in 12 KD versus 60 controls subjects.
28427414RESULTS: Our study shows that IL-21 levels were non-specifically elevated across all febrile children, irrespective of KD diagnosis.
28427414Length of fever prior to sample collection does not correlate with IL-21 levels.
28427414Other inflammatory markers and laboratory values were also compared to IL-21 and show no significant correlation.
28427414CONCLUSIONS: Since IL-21 is elevated non-specifically in this cohort, our data supports that IL-21 is not an appropriate biomarker for diagnosis of KD in North American pediatric populations.
28428203We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells.
28428203TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13.
28467480Assessment of sequence homology and immunologic cross-reactivity between tree shrew (Tupaia belangeri) and human IL-21.
28467480Many studies have indicated that the expression of interleukin-21 (IL-21) is associated with the pathogenesis of certain liver diseases.
28467480However, in alternative animal models of liver diseases, it remains unknown whether the tree shrew could be utilized to analyze the relationship between IL-21 and liver diseases.
28467480Here, the phylogenetic tree, sequence alignment and protein structure model of tree shrew and human IL-21 were analyzed using bioinformatics software.
28467480EGFP-N3/tsIL-21 eukaryotic expression vector of tree shrew IL-21 (tsIL-21) was constructed, and IL-21 expression by the vector-transfected Huh7 cells was evaluated using the newly established quantitative real-time PCR and immunologic protocols for assessing human IL-21.
28467480The tsIL-21 was closely clustered with primate IL-21 rather than rodent IL-21, and it had an alignment of 83.
28467480IL-21 nucleotide sequence and 69.
28467480The profiles of secondary structure, hydrophobicity and surface charge of tsIL-21 were also similar with those of human IL-21.
28467480The tsIL-21 expressed by the vector-transfected Huh7 cells could be identified by their different sources of antibodies against human IL-21, which were all dose-dependent.
28467480Recombinant human IL-21 could induce the change of the cytokine profiles of tree shrew spleen lymphocytes, which showed a higher expression of IL-10 and IFN-γ rather than IL-2, IL-4, IL-17, TNF-a and IL-21 during the five-day stimulation.
28467480The protocols utilized in this study will lead to the experimental feasibility of further IL-21-related studies in vivo.
28468877While CXCR5+ CD4+ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5+ CD4+ T cells were significantly associated with gp120-specific B cell frequencies.
28478440BACKGROUND: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants.
28478440Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons.
28478440OBJECTIVE: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls.
28478440METHODS: Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls.
28478440In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.
28478440Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.
28479106Interleukin-22 (IL-22) belongs to the family of IL-10 cytokines and is involved in a wide number of human diseases, including inflammatory disorders and cancer pathology.
28479106The ligand-receptor complex IL-22/IL-22R plays a key role in several pathways especially in the regulation and resolution of immune responses.
28479106The identification of novel compounds able to modulate IL-22/IL-22R complex could open the route to new therapeutic strategies in multiple human diseases.
28479106Their conformational characterization was carried out through Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies, shedding new light into the features of IL-22 fragments and on structural determinants of IL-22/IL-22R1 recognition.
28479106Finally, several peptides were tested on human keratinocyte cultures for evaluating their ability to mimic the activation of molecular pathways downstream to IL-22R in response to IL-22 binding.
28482850Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics.
28482850Here, we investigated the presence of bioenergetic defects in the brain of transgenic mice expressing human mutant TDP-43 (TDP-43A315T mice), patient derived fibroblasts, and human cells expressing mutant forms of TDP-43.
28482850METHODS: In the brain of TDP-43A315T mice, TDP-43 mutant fibroblasts, and cells expressing mutant TDP-43, we tested several bioenergetics parameters, including mitochondrial respiration, ATP synthesis, and calcium handling.
28482850CONCLUSIONS: While alterations of mitochondrial morphology and dynamics in TDP-43 mutant neurons are well established, the present study did not demonstrate oxidative phosphorylation defects in TDP-43 mutants, in vitro and in vivo.
28489883Functional assays of GC B cells revealed that BMP-7 suppressed the viability-promoting effect of CD40L and IL-21, but had no effect on CD40L- and IL-21-induced differentiation into plasmablasts.
28490810The critical points of our method are pre-stimulation of B cells with IL-21 and CD40-ligand (CD40L), followed by consecutive transfection of highly concentrated Yamanaka factors using a retroviral vector.
28491060So far, the cytokines interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 are used to culture and expand NK cells.
28533995RESULTS: In both CD and UC, interleukin (IL)-12 (p40), IL-18, IL-21 and IL-27 transcript levels were higher than in Control.
28539470Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment.
28539470We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout.
28539470Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro.
28539470Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration.
28558009IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα levels in the aqueous humor and vitreous fluid were measured using a beads-array system.
28558009Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFα levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFα level.
28564491Expression of ICOS and interleukin-21 (IL-21) protein was examined in parotid gland tissue at baseline and after treatment.
28564491Serum levels of IL-21, CXCL13, anti-SSA, and anti-SSB decreased.
28585539IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.
28585539Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours.
28587391The scratching frequency, serum immunoglobulin (Ig)G, IgE, interleukin (IL)-4, IL-10, IL-17, IL-21, interferon-γ and tumor necrosis factor-α levels were assessed at 50 and 98 h.
28607133Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis.
28607133Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion.
28611593Autophagy and Its Impact on Neurodegenerative Diseases: New Roles for TDP-43 and C9orf72.
28611593In this manuscript, we review what is known regarding the autophagic mechanism and discuss the involvement of TDP-43 and C9orf72 in autophagy and their impact on neurodegenerative diseases.
28620644Proinflammatory cytokines IL-6, IL-21, and CD70 were significantly downregulated in group A by 6.
28620653This subset expressed more Bcl-6, c-Maf, and IL-21 than other blood CD4 subsets.
28621822Importazole, an inhibitor of importin-β, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4+ T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression.
28622456CCR9+ T helper cells displayed higher expression of IL-7Rα and secreted higher levels of interferon-γ, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7.
28627158The main purpose of this study was the evaluation of IL-21, as a blood biomarker, for early detection of acute GVHD (aGVHD) in children after HSCT and also the study of human leukocytes antigen (HLA)-C1 polymorphism, as a targeting ligand for NK cells in these patients.
28627158The -8-day samples were analyzed for HLA-C1 polymorphism by PCR-sequence-specific primer technique and pre-transplantation IL-21 assay.
28627158To study the serum levels of IL-21, two blood samples were collected on days +7 and +14 and analyzed by ELISA technique.
28627158On the other hand, the serum levels of IL-21 in children with aGVHD were decreased after transplantation compared to before transplantation.
28627158The serum levels of the IL-21 at 14 days after transplantation had a significant correlation with the occurrence of aGVHD (P=0.
28635548Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma.
28635548METHODS: Peripheral blood neutrophils isolated from asthmatics were stimulated with IL-21, IL-23, and IL-6 cytokines and their ability to produce IL-17A and IL-17F was determined relative to healthy controls.
28635548RESULTS: Stimulating asthmatic neutrophils with IL-21, 23, and 6 enhanced the production of IL-17A and IL-17F at significantly higher levels comparatively to healthy controls.
28635548Stimulating neutrophils with IL-21, IL-23, and IL-6 cytokines enhanced STAT3 phosphorylation, in all cases.
28637276Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients.
28637276Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases.
28637276To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls.
28637276C9orf72 ALS patients.
28637276C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts.
28637276These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases.
28647348We found that most T lymphocytes infiltrating pemphigus vulgaris lesions were CD4+ T helper cells expressing IL-21 and IL-17a but not typical T follicular helper cells expressing CXCR5.
28654841RNA and protein levels of interferon (IFN)-γ, interleukin (IL)-10, IL-17, and IL-21 production.
28654841IFN-γ, IL-10, or IL-21 expression.
28656528Moreover, at mRNA and protein levels, we defined several molecules that may account for the enhanced ability of CHI3L1-KO splenocytes to migrate into target organs and produce IFN-γ and Tfh-related cytokines and chemokines, such as IL-6, IL-21, and CXCL13.
28657833Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17A, IL-21, IL-34, RANKL, survivin, and COMP were selected as candidate biomarkers.