Introduction
This report provides an overview of the most relevant scientific literature for CXCR2. This overview is generated based on the occurrence of CXCR2 and its synonyms in MEDLINE abstracts together with concepts from a number of other ontologies. This is done in a number of ways, shortly described below and described in more details in the respective sections.
  • Based on the occurrence of CXCR2 in these abstracts, other biomedical terms, related to diseases, drugs and pathways that occur in the same abstracts as CXCR2 are retrieved.
  • In addition, the abstracts are scanned for other informative words and visualised in wordclouds.
  • Furthermore, important sentences and facts for CXCR2 are retrieved and shown in a separate table with a link to the original abstracts.
  • Lastly the most relevant abstracts are shown in which CXCR2 and it's synomyms are highlighted.

This report is an interactive HTML report.The hyperlinks in this document link to other sections in the document or to external data sources (which will be opened in a separate window). Most of the tables have options for filtering, searching and exporting the data to Excel.


Related concepts
The following tables show the relation of CXCR2 with biomedical terms representing genes, diseases and pathways. Each relation is described by the number of abstracts in which both terms co-occur and a statistical score. The relations to other genes were obtained by matching to concepts from the human genes database from the website of the Human Genome Nomenclature Committee. The disease concepts for matching were obtained from the Human Disease Ontology website. The ontologies for Drugs and Pathways are TenWise proprietary ontologies (see this page for more information).

Concept ID Hits Score Link
juvenile idiopathic arthritisDERMO:000193010.0Pubmed
myeloproliferative disorderDERMO:000120610.8Pubmed
onchoceriasisDERMO:000278911.5Pubmed
leptospirosisDERMO:000216910.3Pubmed
anaplasmosisDERMO:000216010.9Pubmed
classic kaposi sarcomaDERMO:000105512.0Pubmed
cutaneous T-cell lymphomaDERMO:000012510.4Pubmed
primary cutaneous marginal zone B-cell lymphomaDERMO:000121910.6Pubmed
american trypanosomiasisDERMO:000276810.3Pubmed
ulcerDERMO:00020062-2.0Pubmed
filariasisDERMO:000279010.3Pubmed
schistosomiasisDERMO:000279310.0Pubmed
staphylococcus aureus infectionDERMO:000231521.1Pubmed
mycobacterial infectionDERMO:000231720.9Pubmed
epstein-barr virus infectionDERMO:000231210.3Pubmed
Concept ID Hits Score Link
pancreatic ductal adenocarcinomaDOID:3498111.2Pubmed
bronchiolitisDOID:294240.6Pubmed
autoimmune thyroiditisDOID:718810.0Pubmed
encephalomyelitisDOID:640261.2Pubmed
disseminated intravascular coagulationDOID:1124710.0Pubmed
tuberculosisDOID:399170.0Pubmed
cystitisDOID:167930.4Pubmed
crescentic glomerulonephritisDOID:1313921.1Pubmed
thrombocytopeniaDOID:15881-2.0Pubmed
kidney cancerDOID:26320.4Pubmed
systemic sclerodermaDOID:41870.6Pubmed
pilomatrixomaDOID:537411.1Pubmed
cancerDOID:1623620.4Pubmed
head and neck cancerDOID:1193430.3Pubmed
shipyard eyeDOID:1301411.3Pubmed
Concept ID Hits Score Link
MIR146AHGNC:3153312.5Pubmed
SH2B3HGNC:2960511.8Pubmed
SSTR1HGNC:1133032.0Pubmed
IL23RHGNC:1910031.6Pubmed
EREGHGNC:344311.8Pubmed
DNASE1L3HGNC:295922.7Pubmed
LOXHGNC:666410.6Pubmed
ROS1HGNC:10261270.6Pubmed
IL25HGNC:1376511.3Pubmed
SYKHGNC:1149121.2Pubmed
LPAHGNC:666710.6Pubmed
TSPYL2HGNC:2435811.1Pubmed
OCMHGNC:810521.9Pubmed
CXCL14HGNC:1064042.1Pubmed
TLR2HGNC:11848251.5Pubmed
Concept ID Hits Score Link
JNK signallingPATH_00169041.0Pubmed
AMPK signallingPATH_00169310.7Pubmed
Insulin signallingPATH_00169510.0Pubmed
cAMP signallingPATH_00169410.4Pubmed
MAPK signallingPATH_001697151.0Pubmed
JAK-STAT signallingPATH_00169620.7Pubmed
NOTCH signallingPATH_00169920.4Pubmed
kinase pathwayPATH_00263530.6Pubmed
drug metabolismPATH_00067010.0Pubmed
Akt signallingPATH_001687231.1Pubmed
TLR signallingPATH_00168831.1Pubmed
ERK signallingPATH_00168960.8Pubmed
lysosomal metabolismPATH_00264320.9Pubmed
RAC1 signallingPATH_00166011.3Pubmed
RHOA/ROCK signallingPATH_00166211.4Pubmed
Concept ID Hits Score Link
Leishmania infantumTAX_567110.6Pubmed
Mycoplasma pulmonisTAX_210711.3Pubmed
Trichomonas vaginalisTAX_572210.4Pubmed
Aggregatibacter actinomycetemcomitansTAX_71410.9Pubmed
Plasmodium bergheiTAX_582110.4Pubmed
Staphylococcus aureusTAX_1280150.3Pubmed
Bothrops atroxTAX_872511.7Pubmed
Cyprinus carpioTAX_796251.2Pubmed
Chlamydia psittaciTAX_8355410.9Pubmed
Salmonella entericaTAX_2890110.0Pubmed
Toxoplasma gondiiTAX_581130.4Pubmed
Takifugu rubripesTAX_3103311.4Pubmed
Aspergillus fumigatusTAX_74612850.8Pubmed
Bordetella pertussisTAX_52010.3Pubmed
Citrobacter rodentiumTAX_6782511.2Pubmed
Concept ID Hits Score Link
Decreased platelet glycoprotein IIb-IIIaHP:000197511.4Pubmed
Chronic infectionHP:003103560.8Pubmed
LeukocytosisHP:000197410.0Pubmed
LymphopeniaHP:000188810.3Pubmed
EosinophiliaHP:000188030.3Pubmed
Colon cancerHP:0003003240.8Pubmed
Breast carcinomaHP:0003002390.3Pubmed
NeuroblastomaHP:00030061-2.0Pubmed
Chronic myelogenous leukemiaHP:000550610.0Pubmed
ProstatitisHP:000002420.6Pubmed
Chest painHP:01007491-2.0Pubmed
Bronchiolitis obliteransHP:001194630.9Pubmed
MyelopathyHP:000219610.0Pubmed
AstrocytomaHP:000959240.6Pubmed
TachycardiaHP:00016491-2.0Pubmed

Facts from sentences
The abstracts where CXCR2 is described with other genes, diseases and pathways can be further analyzed to retrieve the exact sentences in which these concepts co-occur with CXCR2. These are shown in the tables below. In each sentence the concepts are highlighted in bold and a link to the abstract in which the sentence was found is provided.

PMIDFACT
25704763We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative B-cells up-regulates CXCR2, but not CXCR1.
25704763These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting.
27802348Interestingly, TLR2 was significantly increased in leptospirosis but identical levels of CD182 and CD11b were detected when compared to controls.
29445104Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.
PMIDFACT
19057948To date, there have not been any CXCR2 SNP associated with pancreatic cancer, but CXCR2 SNP has been postulated to be associated with angiogenesis in systemic sclerosis.
27273823CXCR2 were overexpressed in renal cancer tissues compared with those adjacent normal kidney tissues (P < 0.
24412633CONCLUSIONS: Kidney cancer cells secrete IL-8 to activate the Akt signaling pathway via CXCR2 on MSCs, inducing the migration of MSCs, which may be one of the important mechanisms underlying the homing of MSCs in kidney cancer.
26131180When 46 colorectal cancer patients were divided into groups according to the clinical stage, lymph node metastasis and liver metastasis, we found that CXCR2 expression increased in patients with lymph node metastasis (P < 0.
26414070We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration.
24376747We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines.
19057948We suggest that molecular profiling of each patient's tumor for G691S RET SNP, potentially CXCR2 SNP, and also other yet-to-be identified SNP associated with pancreatic cancer will allow for both improved understanding of individual prognosis and allow for utilization of more personalized, targeted adjuvant therapies.
15880119We show that pepducins derived from either the i1 or i3 intracellular loops of CXCR1 and CXCR2 prevent the IL-8 response of both receptors and reverse the lethal sequelae of sepsis, including disseminated intravascular coagulation and multi-organ failure in mice.
27265504We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.
28964785We show here that the chemokine receptor CXCR2 was overexpressed in breast cancer cell lines and tissues.
26087179We report increased mRNA levels of CXCR1 and CXCR2 in human lung cancer tissues compared to normal counterparts.
27723802We previously demonstrated that CXCR2-driven ovarian cancer progression potentiated NF-κB activation through EGFR-transactivated Akt.
28928867We investigated expression of β-arr2 and CXCR2 in patients with non-small cell lung cancer (NSCLC) and their correlation with lymph node metastasis and prognosis.
22368515We hypothesize that the chemokine receptor, CXCR2, mediates tumor cell invasion and migration and promotes metastasis in breast cancer.
28923105We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer.
29935880We have first evaluated in silico the involvement of MIF, its homologue D-DT, and the receptors CD74, CD44, CXCR2 and CXCR4 in encephalitogenic T cells from a mouse model of MS, the Experimental Allergic Encephalomyelitis (EAE), as well as in circulating T helper cells from MS patients.
26131180We found that the positive rate of CXCR2 protein expression in cancer tissue samples was 69.
25480945We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT vs.
16679868We examined the most representative single nucleotide polymorphisms (SNPs) for the IL-8 and its receptors (CXCR1 and CXCR2) genes, and conducted a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine if these SNPs are associated with susceptibility to and prognosis of prostate cancer.
28575019We conducted this retrospective study to determine the clinicopathologic significance of the CXCL1-CXCR2 axis in human gastric cancer.
23544174We also observe that disrupting the CXCR2 complex, by gene delivery or peptide delivery of exogenous CXCR2 C-tail, significantly inhibits the biologic functions of pancreatic cancer cells (i.
24338377Univariate and multivariate analyses were then performed to determine the relationship between CXCR2 and the clinical characteristics and to analyze whether CXCR2 expression was a significant independent prognostic factor for esophageal cancer patients.
29507619Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity.
24338666Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention.
22617157Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.
21343381To investigate the functional significance of CXCL1 expression, a CXCL1 expression vector and short hairpin RNA targeting the CXCL1 or CXCR2 were transfected into gastric cancer cell lines to examine the biological outcomes of these cells.
24338666To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals.
25339290Thus, the inhibition of K327 ubiquitination might emerge as an effective mean to curb exacerbated CXCR2 signaling in several pathological conditions, such as inflammatory diseases and cancer.
28964785Thus, antagonists of the CXCR2 signaling molecules may be used to treat breast cancer patients particularly with high metastasis and chemoresistance.
29703902Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs.
12626595Thus, CXCR2 may be a relevant target in the pathogenesis of RSV bronchiolitis, since it contributes to mucus production and airway hyperreactivity in our model of RSV infection.
24376747Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-κB activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.
29599927This meta-analysis was aimed to comprehensively summarize the previous studies and to explore the prognostic value of CXCR2 in patients with cancer.
28481874This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer.
29520695These three chemokines were not only involved in endothelial tube formation by binding to the endothelial receptor CXCR2, but also in cervical cancer cell proliferation and clone formation, which were induced by overexpression of AKIP1.
29383101These results demonstrate that CXCR2+ MDSCs accelerate breast cancer progression via directly inducing cancer cell EMT and indirectly promoting T cell exhaustion, suggesting that CXCR2+ MDSCs may be a potential therapeutic target of breast cancer.
21286374These findings indicate a role of BM-derived EPC in pancreatic cancer growth and provide a cellular mechanism for CXCR2 mediated tumor neovascularization.
22494524Therefore, IL-8 and CXCR2 may be important therapeutic targets against colorectal cancer.
28481874Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples.
23425074Then the future possibilities and questions remaining for pharmacological intervention against CXCR2 in pancreatic cancer are explored.
23544174The signaling mediated by the chemokine receptor CXC chemokine receptor 2 (CXCR2) plays an important role in promoting the progression of many cancers, including pancreatic cancer, one of the most lethal human malignancies.
31516616The semi-quantitative analysis revealed that the relative mean density of hepatic IL-8, CXCR1 and CXCR2 staining in liver cancer was significantly increased compared with that in normal liver tissues (P<0.
26657155The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2.
14978086The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR(+) CXC chemokines in a preclinical model of lung cancer.
29399185The present study investigated whether IL-8 and its receptors [IL-8 receptor (IL-8R)A and IL-8RB] contributed to the proliferative and migratory abilities of HeLa cervical cancer cells, and also investigated the potential underlying molecular mechanisms.
26497045The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection.
28575019The overall survival of patients with CXCL1 and CXCR2-positive cancer was poorer than that of the patients with negative cancer.
25627226The nuclear factor kappa beta (NF-kappa B), which regulates the autoimmune and anti-inflammatory responses, is associated with systemic sclerosis (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), just as the CXCR2 e CXCL8 genes.
31516616The mRNA levels of CXCR1 and CXCR2 gradually increased with elevated expression of IL-8 in liver cancer.
12632066The immunohistochemical analysis using specific antibodies demonstrated that positive staining for IL-8, CXCR1 and CXCR2 in surgically resected human pancreatic cancer was 50, 55 and 65%, respectively.
22368515The functional role of CXCR2 in the metastatic phenotype of breast cancer still remains unclear.
15545974The expressions of IL-8 and its receptors, CXCR1 and CXCR2, were examined in a panel of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines.
21387301The expression pattern described in our study, including CXCL1 in LECs and its receptor CXCR2 in cancer cells, offers a promising therapeutic target for gastric cancer.
28575019The effect of gastric cancer cells on the expression of CXCR2 in BM-MCs was examined using diffuse-type gastric cancer cell lines in vitro.
23425074The chemokine receptor CXCR2 has become the subject of much interest recently because of multiple studies indicating its involvement in cancer and inflammatory conditions.
29599927The analyses of different analysis models (univariate or multivariate models), sample size (< 300 or ≥ 300) and ethnicity (Asian and Caucasian) have indicated the negative impact of CXCR2 over-expression on survival of patients with cancer.
22391039The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo.
31516616Taken together, these results indicated that IL-8 promotes liver cancer cell migration via CXCR1 and CXCR2 and that targeting the CXCR1/2 may be a potential strategy for liver cancer treatment.
27723802Taken together, the progression of ovarian cancer in the peritoneal cavity involves NF-κB-mediated CCL20 as a main chemokine network, which is potentiated by CXCR2 expression.
22617157Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth.
22922255Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.
22494524Several studies have demonstrated that IL-8 and its receptor CXCR2 are two of the most significantly upregulated chemokines in colorectal cancer.
25541970Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1) were significantly associated with rectal cancer (PARTP < 0.
25484047SUMMARY: The CXC chemokine receptor-2 (CXCR2) is a member of the large 'family A' of G-protein-coupled-receptors and is overexpressed in various types of cancer cells.
30135194SC-derived CXCL5 was responsible for EMT in lung cancer cells, as the inhibition of CXCL5 or its receptor CXCR2 reduced SC-induced expression of Snail and Twist and reduced motility in tumor cells.
23425074Research now indicates that CXCR2 and its ligands are intimately involved in tumor regulation and growth and that inhibition of its function shows promising results in multiple cancer types, including pancreatic cancer.
28575019RESULTS: The expression of CXCL1 in cancer cells was correlated with T invasion (T2-T4), lymph node metastasis, lymphatic invasion, venous invasion, peritoneal cytology, peritoneal metastasis and CXCR2 expression in stromal cells.
21343381RESULTS: The expression of CXCL1 and CXCR2 was higher in gastric cancer tissues compared with adjacent noncancerous tissues.
20505188RESULTS: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice.
30796034RESULTS: CXCR2 expression is associated with the prognosis of patients with gastric cancer (P = 0.
28214673RESULTS: CXCR2 expression had no impacts on predicting prognosis, but low DARC expression in cancer cells was an independent risk factor for poor prognosis.
22368515Previous studies have shown that CXCR2 expression is upregulated in malignant breast cancer tissues but not in benign ductal epithelial samples.
28964785Poor outcomes were associated with the high expression of CXCR2 or COX2 while favorable survivals were associated with the high expression of P85α, AKT1, or E-cadherin in all cancer patients.
22370847Patients with tuberculosis and latent Mycobacterium tuberculosis infection were assessed for the spontaneous expression of CXCR1 (CD128) and CXCR2 on lymphocytes and monocytes.
24376747Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells.
15930347PURPOSE: We characterized interleukin-8 (IL-8) and IL-8 receptor expression (CXCR1 and CXCR2) in prostate cancer to address their significance to this disease.
28575019PURPOSE: It was reported that the chemokine (C-X-C motif) ligand 1 (CXCL1) from cancer cells stimulated the recruitment of bone marrow-derived mesenchymal cells (BM-MCs) into tumor stroma via chemokine (C-X-C motif) receptor 2 (CXCR2) signaling.
20505188PURPOSE: Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive.
21343381Our studies were designed to clarify the CXCL1 and CXCR2 expression patterns and to explore their potential role in gastric cancer.
26087179Our results suggest that G31P blockage of CXCR1 and CXCR2 can inhibit human lung cancer cell growth and metastasis, which offers potential therapeutic opportunities.
26414070Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer.
28481874Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
22391039Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway.
25480945Our findings demonstrate a function for a 3'UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer.
30871004Our data suggest the importance of both tumor cell- and host-derived CXCR2 signaling in the bone metastasis of breast cancer cells.
22815748Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.
31654638Our aim was to discover the role of interleukin 17 (IL-17), CXCR2 ligands, and cancer-associated neutrophils in chemotherapy resistance and metastasis in breast cancer.
25580640Our aim was to analyze the potential role of chemokine receptors CXCR2 and CXCR4 signalling pathways in liver metastatic colorectal cancer (CRC) relapse.
22674296Only SNPs from genes within the IL-8 pathway (IL8, CXCR1 and CXCR2) showed a significant association with both colon and rectal cancer risk.
30796034Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of gastric cancer cells.
10902769OBJECTIVE: To search for single-nucleotide polymorphisms in the interleukin-8 (IL-8) and IL-8 receptor CXCR-1 and CXCR-2 genes, and to compare their distribution among patients with systemic sclerosis (SSc) with fibrosing alveolitis (FASSc) or without fibrosing alveolitis (NFASSc), or patients with cryptogenic fibrosing alveolitis (CFA), and normal healthy subjects.
22617157Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth.
25022956Moreover, CXCR1 and CXCR2 expression was associated with tumor differentiations, advanced clinical stages, lymph node, and distant metastasis of gastric cancer.
30796034Macrophages are the major sources of CXCL1 and CXCL5 in the gastric cancer microenvironment, and promote migration of gastric cancer cells through activating a CXCR2/STAT3 feed-forward loop.
29545333MIRTX directly targeted the 3'-UTR of CXCR2 and PIK3R1 mRNA and suppressed the NF-κB signaling pathway in KRAS-mutated colorectal cancer cells.
28575019METHODS: The correlations between the clinicopathological features of 270 primary gastric carcinomas and CXCL1 in cancer cells and CXCR2 in stromal cells were analyzed in immunohistochemical studies.
26497045METHODS: Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center.
26837773METHODS: Expression levels of CXCL3 and CXCR2 in prostate cancer cell lines (PC-3, DU145 and LNCaP), immortalized prostate stromal cell line (WPMY-1) and immortalized prostate epithelial cell line (RWPE-1) were investigated by RT-PCR, ELISA and western blot, whereas expression levels of CXCL3 in a prostate tissue microarray were detected by immunohistochemistry.
25022956MATERIALS AND METHODS: A total of 172 cases of gastric cancer tissue specimens were collected for immunohistochemical analysis of CXCR1, CXCR2, and MMP9 expression.
30796034Inhibiting CXCR2 pathway of gastric cancer cells can suppress migration and metastasis of gastric cancer in vitro and in vivo.
10950785In whole blood in vitro, LPS, lipoarabinomannan from Mycobacterium tuberculosis, and lipoteichoic acid from Staphylococcus aureus reduced expression of CXCR2 but not of CXCR1.
25022956In vitro study showed that levels of CXCR1 and CXCR2 proteins were associated with the capacity of gastric cancer cell migration, while knockdown of their expression inhibited gastric cancer cell migration and invasion abilities in vitro.
28481874In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis.
30659170In this study, we further discovered that PDAC and cancer-associated fibroblast (CAF) accelerated each other's invasion and migration through the CXC chemokines-receptor (CXCLs-CXCR2) axis.
16679868In this population, we observed no strong association between the SNPs for IL-8 -251 (A-->T), CXCR1 +860 (C-->G) and CXCR2 -1010 (A-->G) and either the subsequent risk of prostate cancer or individual prognostic factors among cases.
24359571In the total population, inheritance of the IL1R2 rs11886877 AA, IL8RB rs11574752 AA, TNF rs1800629 GA + AA, and TNF rs673 GA genotypes modestly increased prostate cancer risk by 1.
26131180In the present study, we detected CXC chemokine receptor-2 (CXCR2) CXCR2 expression in patients with colorectal cancer (CRC) and investigated the correlation of CXCR2 expression with clinicopathological variables.
31516616In the present study, it was shown that the mRNA levels of IL-8, CXCR1 and CXCR2 were increased in peripheral blood mononuclear cells from patients with liver cancer compared with those from patients with cirrhosis or normal controls (P<0.
23544174In summary, our results suggest the existence of a physical and functional coupling of CXCR2 and PLC-β3 mediated through NHERF1, forming a macromolecular complex that is critical for efficient and specific CXCR2 signaling in pancreatic cancer progression.
30135194In summary, SCs can regulate the CXCL5/CXCR2/PI3K/AKT/GSK-3β/Snail-Twist pathway to promote EMT, invasiveness, and metastatic potential of lung cancer cells.
21387301In human gastric cancer specimens, CXCR2 expression was positively correlated with TNM (Tumor, node, metastasis) stage and lymphatic vessel density.
10950785In healthy subjects, LPS induced a transient decrease in granulocyte CXCR1 and CXCR2 expression, whereas in tuberculosis patients, only CXCR2 showed reduced levels.
30219773In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that the genetic deletion of CerS2 suppresses EAE pathology by interaction with granulocyte-colony stimulating factor (G-CSF) signaling and CXC motif chemokine receptor 2 (CXCR2) expression, leading to impaired neutrophil migration.
15930347In contrast, membranous expression of IL-8, CXCR1, and CXCR2 was nonapical in cancer cells of Gleason pattern 3 and 4, whereas circumferential expression was present in Gleason pattern 5 and androgen-independent prostate cancer.
17949231In conclusion, IL-8 -251T/A polymorphism is associated with development of invasive ductal carcinoma type of breast cancer while CXCR2 +1208C/T polymorphism may affect the disease progression.
22391039In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment.
19057948In a preclinical corneal micropocket assay, treatment of pancreatic cancer cell lines that express CXCR2 with anti-CXCR2 antibody inhibited angiogenesis.
22789011Immunohistochemical analysis of human breast tumor samples also confirmed the importance of the hPTTG1/CXCR2 axis in promoting breast cancer metastasis.
27324095INTRODUCTION: CXCR2, the receptor of the CXC chemokines, plays a critical role in cell migration and invasion in many types of cancer.
17949231IL-8 -251T/A polymorphism and the CXCR2 +1208 C/T polymorphism have a role in breast cancer susceptibility.
30796034However, the underlying mechanism of CXCR2-mediated cross-talk between gastric cancer cells and macrophages still remains unclear.
26837773However, the investigations about CXCL3/CXCR2 axis in prostate cancer have been poorly involved.
31516616However, the expression and functional roles of IL-8 and its receptors, CXC chemokine receptor (CXCR) 1 and CXCR2 in the progression of liver cancer remain to be fully elucidated.
24338377However, expression of CXC chemokines type 2 (CXCR2) and its association with clinicopathological characters and patients' prognosis in esophageal cancer are scarcely reported.
27297979High expression levels of CXCR2 and CXCR3 in cancer tissues correlated with tumour progression of renal cell carcinoma.
28415702Herein, we identified the prognostic significance of CXCR2 in colorectal cancer patients.
26837773Herein we firstly reported our studies on the expression and biological roles of CXCL3 and CXCR2 in prostate cancer.
24117268Here, we investigated the roles of chemokine receptor 2 (CXCR2) and transient receptor potential vanilloid 1 (TRPV1) channels in a rat model of cyclophosphamide-induced cystitis.
20505188Here, we investigated the role of CXCR2 in human ovarian cancer.
27723802Here, we identified the chemokine signature involved in CXCR2-driven ovarian cancer progression using a mouse peritoneal xenograft model for ovarian cancer spreading with CXCR2-negative (SKA) and positive (SKCXCR2) cells generated previously from parental SKOV-3 cells.
23204236Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells.
22617157Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis.
23544174Here, using a series of biochemical assays, we demonstrate that CXCR2 is physically coupled to its downstream effector phospholipase C-β3 (PLC-β3) that is mediated by PDZ scaffold protein Na(+)/H(+) exchange regulatory factor 1 (NHERF1) into a macromolecular signaling complex both in vitro and in pancreatic cancer cells.
27265504Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells.
29383101Here we identify that Ly6GmiLy6CloCD11b+CXCR2+ subpopulation (named CXCR2+ MDSCs) are predominately expanded and recruited in systemic and local tumor microenvironment during breast cancer progression and metastasis.
31043491Genetic ablation of the chemokine receptor Cxcr2 inhibited cancer stem cell expansion and tumorigenesis via senescence.
21343381Furthermore, cancer cells expressing CXCL1 stably exhibited an increase in their migration and invasion ability, whereas CXCL1 or CXCR2 depletion significantly reduced the migration and invasion ability of each cell line.
29383101Furthermore, CXCR2+ MDSCs induce epithelial mesenchymal transition (EMT) of breast cancer cells via IL-6.
28964785Further study suggested that AKT1 and cyclooxygenase-2 (COX2; PTGS2) might mediate the CXCR2 signaling to inversely control the breast cancer metastasis and chemoresistance through the regulation of EMT, apoptosis, and senescence.
20540789Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis.
28481874Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis.
25022956Expression of CXCR1 and CXCR2 proteins was knocked in or down using their cDNA and shRNA, respectively, in gastric cancer cell lines to assess the changed cell phenotypes and gene expression.
30796034Experimental Design: The expression of CXCR2 and its ligands in 155 human gastric cancer tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated.
15930347Each of IL-8, CXCR1, and CXCR2 were also increasingly localized to the cytoplasm of cancer cells in correlation with advancing stage of disease.
20505188EXPERIMENTAL DESIGN: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3.
30796034ELISA, transwell, cell viability assay, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting gastric cancer growth and metastasis.
23544174Disrupting this CXCR2 complex could represent a novel and effective treatment strategy against pancreatic cancer.
29599927Conclusions: CXCR2 is an unfavorable predictor in terms of OS and RFS in patients with cancer except for digestive tract cancer and is related with poorer prognostic.
29507619Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.
31654638Collectively, these data demonstrate that the IL-17-CXCR2 axis facilitates the recruitment of neutrophils to the tumor sites, thus allowing them to play a cancer-promoting role in cancer progression.
23425074Clinically speaking, CXCR2 is an exciting potential target for pancreatic cancer; however, CXCR2 is functionally important for multiple processes and therapeutic options would benefit from further work toward understanding of these roles as well as structural and target specificity.
28481874CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues.
20610741CXCR2-positive neutrophils facilitate inflammatory demyelination in demyelination models such as experimental autoimmune encephalomyelitis (EAE) and cuprizone intoxication.
26231560CXCR2, an interleukin-8 receptor, is reportedly expressed in several carcinomas, and interleukin-8 signaling promotes cancer cell proliferation.
25580640CXCR2, CXCR4, and their chemokine ligands were evaluated in liver metastases of colorectal cancer in order to study their correlation with overall and disease-free survival of patients having received, or not received, a neoadjuvant chemotherapy regimen.
20505188CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis.
28964785CXCR2 promoted anti-apoptosis, anti-senescence, and epithelial-to-mesenchymal transition (EMT) of breast cancer cells, leading to the enhanced metastasis and chemoresistance.
30233217CXCR2 is involved in breast cancer metastasis, treatment resistance, and recurrence and has positive cross-talk with known breast CSC protein markers.
19057948CXCR2 is an important mediator of CXC chemokine-induced angiogenesis and is upregulated in pancreatic cancer.
23204236CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis.
30233217CXCR2 expression decreased in estrogen receptor-negative or HER2-negative breast cancer, but not progesterone receptor-negative counterparts.
26153616CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer.
27446456CXCR2 and IL-22BP protein expression was analyzed by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction assays in gastric cancer (GC) tissue, additionally confirmed via western blotting and immunocytochemical analysis in the MKN-45, BGC-823 and SGC-7901 cell lines.
30135194CXCL5/CXCR2 binding activated the PI3K/AKT/GSK-3β/Snail-Twist signaling pathway in lung cancer cells, and the PI3K inhibitor blocked CXCL5-dependent phosphorylation of AKT and GSK-3β, reduced expression of Snail/Twist, and limited tumor cell invasiveness.
27737879CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas.
22274915CXC-chemokine receptor type 2 (CXCR2) was reported to play critical roles in angiogenesis, tumorigenesis, and metastasis of several cancers such as colon cancer, melanoma, lung cancer, and so on.
22368515CONCLUSIONS: Together, these results suggest that CXCR2 may play a critical role in breast cancer invasion and metastasis.
25022956CONCLUSIONS: These findings suggest that CXCR1 and CXCR2 play an important role in gastric cancer progression.
30796034CONCLUSIONS: Our study suggested a previously uncharacterized mechanism through which gastric cancer cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat gastric cancer.
26231560CONCLUSIONS: Our results suggest that the patients with CXCR2-positive esophageal cancer who develop postoperative complications have a poor prognosis and should be carefully followed.
20505188CONCLUSIONS: Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-kappaB, in ovarian cancer.
24965032CONCLUSIONS: Functional CXCR1 and CXCR2 exist on normal and cancerous oral epithelial cells, and our data suggests a role for these receptors in oral cancer biology.
28214673CONCLUSIONS: DARC expressing in cancer cells inhibits PDAC progression by suppressing STAT3 activation through the inhibition of CXCR2 signaling.
24117268CONCLUSIONS AND IMPLICATIONS: CXCR2 and TRPV1 channels play important roles in cyclophosphamide-induced cystitis in rats and could provide potential therapeutic targets for cystitis.
28575019CONCLUSION: The expressions of CXCL1 in cancer cells and CXCR2 in stromal cells are useful prognostic factors for gastric cancer patients.
20540789CONCLUSION: Our results indicated that the polymorphisms in IL-8 and CXCR2 genes are associated with increased breast cancer risk, as well as disease progress, supporting our hypothesis for IL-8 and ELR+CXC chemokine receptor (CXCR2) involvement in breast cancer pathogenesis.
26837773CONCLUSION: Our findings suggest that CXCL3 and its receptor CXCR2 are overexpressed in prostate cancer cells, prostate epithelial cells and prostate cancer tissues, which may play multiple roles in prostate cancer progression and metastasis.
26497045CONCLUSION: Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients.
28575019Both CXCL1 expression in cancer cells and CXCR2 expression in stromal cells were independent prognostic factors for gastric cancer patients.
21356384Blockade of either CXCL5 or CXCR2 may be a critical adjunct antiangiogenic therapy against pancreatic cancer.
21356384Blockade of CXCL5 or its receptor CXCR2 by small-interfering RNA knockdown or antibody neutralization attenuated human pancreatic cancer growth in a nude mouse model.
29383101Besides, CXCR2+ MDSCs promote breast cancer growth and metastasis to lung and/or lymph node in vivo.
28928867Background : Although β-arrestin-2 (β-arr2) and CXCR2 have been shown to affect various malignant tumors, their exact roles in lung cancer remain unclear.
29599927Background & Aims: Quite a few studies had investigated the correlation between CXC chemokine receptor 2 (CXCR2) and cancer.
26668819BACKGROUND: Residual CXCR2 expression on CNS cells in Cxcr2 (+/-) →Cxcr2 (-/-) chimeric animals slowed remyelination after both experimental autoimmune encephalomyelitis and cuprizone-induced demyelination.
23972657BACKGROUND: CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells.
26497045BACKGROUND: CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells.
28964785Analyses of clinical data indicate that the high expression of CXCR2 was correlated with the high expression of COX2 and the low expression of AKT1, P85α, E-cadherin, and β-catenin in cancer tissues.
28964785All these data suggest that CXCR2 promotes breast cancer metastasis and chemoresistance via suppressing AKT1 and activating COX2.
22674296After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk.
31562303Additional studies using CXCL5 recombinant protein suggest that CXCL5 is sufficient to promote breast cancer cell proliferation and colonization in bone, while inhibition of its receptor CXCR2 with an antagonist blocks proliferation of metastatic cancer cells.
23425074AREAS COVERED: In this study, the authors review basic molecular and structural details of CXCR2, as well as the known functions of CXCR2 and several of its ligands in inflammation and cancer biology with specific attention to pancreatic cancer.
26391267AIM: To investigate the diversity of the proinflammatory genes IL8, its receptors and PTGS2 in Amerindians; to test whether candidate SNPs in these genes are associated with gastric cancer in an admixed population with high Amerindian ancestry from Lima, Peru; and to assess whether an IL8RB promoter-derived haplotype affects gene expression.
PMIDFACT
19293401We then asked if TLR2-mediated sensing of TCT by innate sentinel cells could induce secretion of CXC chemokines, which would then evoke neutrophil-dependent plasma leakage via the CXCR2/B(2)R pathway.
27016001We speculated that impaired neutrophil chemotaxis in sepsis was probably mediated by the TLR2-CXCR2 pathway.
21521824We report that 1) LPA injection into the air pouch induced leukocyte recruitment and that both LPA(1) and LPA(3) were involved in this process; 2) LPA stimulated the release of the pro-inflammatory chemokines keratinocyte-derived chemokine (KC) and interferon-inducible protein-10 (IP-10) in the air pouch; 3) tumor necrosis factor-α (TNF-α) injected into the air pouch prior to LPA strongly potentiated LPA-mediated secretion of cytokines/chemokines, including KC, IL-6, and IP-10, which preceded the enhanced leukocyte influx; and 4) blocking CXCR2 significantly reduced leukocyte infiltration.
28827732Twenty-two variants from 21 genes (APEX1 rs1130409 and rs1760944, ATM rs664677, AXIN2 rs2240308, CHRNA3 rs6495309, CHRNA5 rs16969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1 rs4646903, CYP2E1 rs6413432, ERCC1 rs11615, ERCC2 rs13181, FGFR4 rs351855, HYKK rs931794, MIR146A rs2910164, MIR196A2 rs11614913, OGG1 rs1052133, PON1 rs662, REV3L rs462779, SOD2 rs4880, TERT rs2736098, and TP53 rs1042522) showed significant associations with lung cancer susceptibility with strong cumulative epidemiological evidence.
16516978To test this hypothesis, neutrophils were isolated from cows representing each CXCR2 +777 genotype (GG, GC or CC) and tested for suppression of apoptosis, reactive oxygen species (ROS) generation, glutathione levels, and bactericidal activity.
9234898To illustrate the broad applicability of this technique, we have presented data from cell lines expressing a glycoprotein hormone receptor for follicle-stimulating hormone (FSHR), CXC- (CXCR-2), and CC-chemokine (CCR-1) receptors and peptide receptors from the somatostatin (SSTR1, 2, 5) and neuropeptide Y (NPY-Y2, -Y4 Rs) families.
24728213This study aimed to evaluate the expression of CD14 receptors on monocytes; CD66b and CXCR2 receptors on neutrophils; and TLR2, TLR4, TLR5, TLR9, and CD11b receptors on both cell types of septic patients.
15385471These were (i) a knockout of the gp91(phox) component of NADPH oxidase, in which reactive oxygen species (ROS) production is greatly reduced; (ii) a double knockout of gp91(phox) and inducible nitric oxide synthase, in which ROS and nitric oxide production is greatly decreased; (iii) a knockout of the chemokine receptor CXCR2, in which accumulation of intra-alveolar neutrophils is severely diminished; and (iv) antibody depletion of circulating neutrophils in wild-type mice with the monoclonal antibody RB6.
21703600The expression values of the CD11b, CD11c, CD14, CD18, CD35, CD181, CD182, CD282 and CD284 receptors on peripheral human monocytes and granulocytes was established.
29120053The expanded G-MDSCs also show increased CXCR2 expression, which guides egress out of BM, and produce arginase-1 and ROS upon encountering antigen-activated T cells.
16625117TLR2, TLR4, MIP2, CXCR2, pp38, and ERK expression were evaluated.
19293401TLR2, CXCR2, and B(2)R in edema development.
19234125TLR2 deficiency prevented the down-regulation of CXCR2 and failure of neutrophil migration.
26271598ROS production were established using CXCL8 or CXCL1 to evaluate dual CXCR1/2- or selective CXCR2-dependent activities.
19156404Pretreatment with AT1 receptor blocker (ARB) losartan (1, 3, 10 microM) attenuated monocytic adhesiveness elicited by ADMA and downregulated the expression of CCR2 and CXCR2 mRNA, accompanied by a significant decrease in ROS generation and NF-kappaB activity and expression.
24692851Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed.
31494226Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002.
22660232METHODS: Altogether ten Single Nucleotide Polymorphisms (SNPs) of IL17A (rs2275913), IL17F (rs763780), IL4 (rs2243250), IL12A (rs583911), IL12B (rs3212227 and (rs17860508), IL23R (rs7517847), CXCL1 (rs4074), CXCL5 (rs425535) and CXCR2 (rs2230054) genes were genotyped by PCR with sequence specific primers (SSP) in 98 patients with PJI and two control groups 1) an aseptic TJA control (253 patients with TJA that did not develop PJI at least 6 yrs.
27802348Interestingly, TLR2 was significantly increased in leptospirosis but identical levels of CD182 and CD11b were detected when compared to controls.
19033535Inhibition of TLR2, 4, and 9 prevented the increase in oxidative burst and the decrease in CXCR1 and CXCR2 expression but did not prevent phagocytic dysfunction.
19234125In vitro, the TLR2 agonist lipoteichoic acid (LTA) down-regulated CXCR2 expression and markedly inhibited the neutrophil chemotaxis and actin polymerization induced by CXCL2.
16625117In experiment 4, reactive oxygen species production, CXCR2, MIP2, TLR2, and TLR4 expression of bone marrow neutrophil from mice receiving hypertonic saline or saline treatment after thermal injury were evaluated.
25930080In a chronic-binge ethanol-feeding model, the TLR2 and TLR9-dependent MyD88-dependent pathway mediates CXCL1 production in hepatocytes and HSCs; the CXCL1 then promotes neutrophil infiltration into the liver via CXCR2, resulting in the development of alcohol-mediated liver injury.
23348516INTERVENTIONS: Twenty milliliters of whole heparinized blood was used for in vitro studies including neutrophil viability and apoptosis, surface expression of CD16, Toll-like receptors () 4 and TLR2, CD14, MD-2, HLA-DP,-DQ and -DR, and CXCR2, chemotaxis, phagocytosis, bacterial killing, and tumor necrosis factor-α/interleukin-10 baseline intracellular cytokine levels.
26432841III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1β) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation.
16625117Hypertonic saline increased the phagocytic activity and TLR2, TLR4, CXCR2, pp38, and P44/42 expression of peritoneal cells.
16625117Hypertonic saline increased bacterial clearance, phagocytic activity, and TLR2, TLR4, CXCR2, pp38, and p44/42 expression of peritoneal cells.
28663317Following treatment, CLC and CPA3 gene expression was reduced, whereas DNASE1L3, IL1B, ALPL and CXCR2 expression remained unchanged.
30443903Flow experiments using dihydroethidium-preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8.
24779584Expression of IL-8 receptors (CXCR1 and CXCR2) and the LPS receptor TLR4 was similar on neutrophils from young and old subjects, and neutrophils challenged with phorbol-12-myristate-13-acetate (PMA) showed no age-associated differences in ROS or NET production.
17551258Exogenous ADMA (30 microM) also increased ROS generation and the levels of TNF-alpha and IL-8, decreased the levels of nitrite/nitrate, upregulated CXCR2 gene expression, increased endothelial cell binding with monocytes and activated the NF-kappaB pathway, which was inhibited by pretreatment with losartan or L-arginine.
15973123DNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4.
22660232CONCLUSIONS: We cannot nominate any of studied polymorphisms in IL17A, IL17F, IL4, IL12A, IL12B, IL23R, CXCL1, CXCL5 and CXCR2 genes as risk factors for PJI in the Czech TJA patients examined.
21703600CD282 on granulocytes was observed as CD181, CD182 and CD284 on monocytes.
27466507CCRL1, CCBP2, CMKLR1, XCR1 and CXCR2 and 6 chemokine genes (CCL13, CCL27, CXCL14, CMTM1, CMTM2, CKLF) were more highly expressed in tissues of patients without tumor recurrence/perineural invasion compared to those with tumor recurrence.
27016001By contrast, in septic neutrophils, the expression of TLR2 was significantly increased, whereas the expression of CXCR2 was significantly decreased.
30353422A804598 treatment reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of number of inflammatory markers, including IL-1β, iNOS, CXCR2, and components of inflammatory signaling pathways, such as TLR2, CASP1, NF-kB1 and CREB1, as well in the protein levels of pro-IL-1β and Nf-kB1.
PMIDFACT
15608143These data demonstrate that both MEK1-ERK1/2 and PI3K-Akt signaling pathways are involved in CXCR2-mediated neuroprotection and that multiple downstream signaling events, including RSKs, Bad, and CREB, are activated in this process.
29229683Therefore, we demonstrated that MSCs promoted EPC migration via activating CXCR2 and its downstream Src-PKL/Vav2-Rac1 signaling pathway.
24841946The data obtained from LC-MS/MS, combined with database searches and protein assembly algorithms, allowed us to address significant differences in protein spectral counts and identify unique pathways that may be a component of the induction of the signature inflammatory cytokine response against BECs, including the Notch signaling pathway, interleukin (IL)8, IL6, CXCR2, and integrin signaling.
20702723Taken together, these data show that CXCL1 functions through CXCR2 to transactivate the EGFR by proteolytic cleavage of HB-EGF, leading to activation of MAPK signalling and increased proliferation of EOC cells.
20214572Receptor internalization was closely coupled with ERK signalling both when analyzed in regard of stimulation by physiological CXCR2 ligands and when observed in the presence of antagonistic test compounds.
30016780RESULTS: IL-8 may trigger in vitro migration of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway.
26058729Our mechanistic studies show that CXCL5 contributes to BCa migration and invasion by binding to its receptor, CXCR2, leading to the upregulation of MMP2/MMP9 by activating PI3K/AKT signaling.
26402907Our data provide the first-line evidence that, by repressing GRK2, miR-K3 facilitates cell migration and invasion via activation of CXCR2/AKT signaling, which likely contribute to the dissemination of KSHV-induced tumors.
22391039Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-κB/mitogen-activated protein kinase (MAPK)/AKT pathway.
30446590Mechanistically, DLBCL-derived IL8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38, and ERK signaling.
26364720MALAT1 silencing significantly downregulated the expression of the miR-22-3p target gene CXCR2 via reversing the effect of the miR-22-3p, resulting in the aggravation of Oxidized low-density lipoprotein (ox-LDL)-induced endothelial injury; this process was associated with the AKT pathway.
30016780IL-8 induces chondrogenic differentiation of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway in vitro and in vivo.
25480945Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling.
26402907Finally, deletion of miR-K3 from the KSHV genome abrogated its effect on the GRK2/CXCR2/AKT pathway and KSHV-induced migration and invasion.
27324095DISCUSSION: Our results suggest that the decreased CXCR2 may contribute to the development of preeclampsia through impairing trophoblast invasion by down-regulating MMP-2 and MMP-9 via the Akt signaling pathway.
11504781Clearance of this chemokine may be mediated by its pharmacologic receptor, CXCR2, via endocytosis with subsequent lysosomal degradation, as has been observed for several growth and hematopoietic factors.
25135253CXCR2-dependent chondrocyte homeostasis was mediated by AKT signalling since forced expression of constitutively active AKT rescued the expression of phenotypic markers and the apoptosis induced by CXCR2 blockade.
24412633CONCLUSIONS: Kidney cancer cells secrete IL-8 to activate the Akt signaling pathway via CXCR2 on MSCs, inducing the migration of MSCs, which may be one of the important mechanisms underlying the homing of MSCs in kidney cancer.
30016780CONCLUSIONS: IL-8 enhances therapeutic effects of MSCs on bone regeneration via CXCR2-mediated PI3k/Akt signaling pathway.
30340844CONCLUSION: In conclusion, our study demonstrated that SCH-527123, a small-molecule antagonist for CXCR1 and CXCR2 inhibited cell proliferation, migration and invasion in melanoma via PI3K/AKT pathway.
PMIDFACT
10570298We hypothesized that interaction of these ligands with CXC chemokine receptor-2 (CXCR2), their sole murine receptor, is a major component of neutrophil-dependent pulmonary host defense against Aspergillus fumigatus.
17034853We applied real time quantitative PCR (RQ-PCR) to measure the expression of the pro-inflammatory cytokines CXCa, CXCb, interleukin (IL)1-beta, tumor necrosis factor alpha (TNFalpha), and the receptors IL1R1, CXCR1 and CXCR2 in skin of Cyprinus carpio after mechanical injury.
11801688Therefore, the present study addressed the role of CXCR2 during Aspergillus fumigatus-induced asthma.
30863202Nevertheless, Aggregatibacter actinomycetemcomitans was detected more frequently in men positive for the C allele of the CXCR2 +785C/T polymorphism (61.
10950785In whole blood in vitro, LPS, lipoarabinomannan from Mycobacterium tuberculosis, and lipoteichoic acid from Staphylococcus aureus reduced expression of CXCR2 but not of CXCR1.
11714818In this work, mice deficient in expression of the chemokine receptor CXCR2 were infected with Toxoplasma gondii and the outcome was monitored.
PMIDFACT
25682075We used mouse breast carcinoma cells metastasize to brain (4TBM), liver (4TLM), and heart (4THM) and explored the extra- and intracellular mechanisms effecting MIP-2 secretion using CXCR2 antagonist and inhibitors of downstream signaling molecules.
28964785We show here that the chemokine receptor CXCR2 was overexpressed in breast cancer cell lines and tissues.
22368515We hypothesize that the chemokine receptor, CXCR2, mediates tumor cell invasion and migration and promotes metastasis in breast cancer.
25682075We aimed to explore regulation of activity of CXCR2 and its ligand, MIP-2, in metastatic breast carcinoma.
24338666Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention.
22617157Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.
26797460Together, our data suggest chemotherapy-specific differential regulation of CXCR2 ligands, stem cell-like and mesenchymal phenotypes, and enhanced metastasis in drug-resistant cells and targeting CXCR2 signaling, may help circumvent therapy resistance in breast cancer.
24338666To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals.
28964785Thus, antagonists of the CXCR2 signaling molecules may be used to treat breast cancer patients particularly with high metastasis and chemoresistance.
21035946These studies demonstrate the important role of CXCR2/1 in colon cancer metastasis and that inhibition of CXCR2 and CXCR1, small molecule antagonists provides a novel therapeutic strategy.
29383101These results demonstrate that CXCR2+ MDSCs accelerate breast cancer progression via directly inducing cancer cell EMT and indirectly promoting T cell exhaustion, suggesting that CXCR2+ MDSCs may be a potential therapeutic target of breast cancer.
23272179These observations indicate a crucial role for TANs in the initiation and progression of CAC and suggest that the CXCL2-CXCR2 axis might be useful in reducing the risk of UC-associated colon cancer.
15787094These data demonstrate that the constitutive expression of CXCL1 and its receptor CXCR2 is associated with metastatic potential and modulates colon cancer cell proliferation and an invasive phenotype.
20540789The presence of two higher risk genotypes (the TA and TT in IL-8, and the TT in CXCR2) significantly increased the risk of developing breast carcinoma (adjusted OR = 4.
22368515The functional role of CXCR2 in the metastatic phenotype of breast cancer still remains unclear.
20540789The CXCR2 (+ 1208) T allele manifested a significant association with an aggressive phenotype of breast carcinoma as defined by a large tumor size, a high histological grade, and auxiliary's lymph node metastasis.
22617157Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth.
27578214Studies have suggested that CXCL8 and its cognate receptors, C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2), mediate the initiation and development of various cancers including breast cancer, prostate cancer, lung cancer, colorectal carcinoma and melanoma.
27959418Recent studies have demonstrated that the CXCL7/CXCR2 signaling plays a promoting role in several common malignancies, including lung, renal, colon, and breast cancer.
9334359RNA for IL-8-binding chemokine receptors CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC) were found in all astrocytoma grades by reverse transcription/PCR analysis.
22368515Previous studies have shown that CXCR2 expression is upregulated in malignant breast cancer tissues but not in benign ductal epithelial samples.
22986777Our results showed for the first time that triptolide inhibited the expression of CXCR2 and presenilin in a neuroblastoma cell line SHSY5Ysw.
30871004Our data suggest the importance of both tumor cell- and host-derived CXCR2 signaling in the bone metastasis of breast cancer cells.
31654638Our aim was to discover the role of interleukin 17 (IL-17), CXCR2 ligands, and cancer-associated neutrophils in chemotherapy resistance and metastasis in breast cancer.
20540789Moreover, the presence of the IL-8 (-251) A and/or the CXCR2 (+ 1208) T allele showed a significant association with a decreased overall survival and disease-free survival in breast carcinoma patients.
22617157Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth.
20540789METHODS: We used the allele-specific polymerase chain reaction to characterize the variation of IL-8 and CXCR2 for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects.
20596532METHODOLOGY/PRINCIPAL FINDINGS: JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR+ chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection.
25511644In this report, we hypothesized that host-derived Cxcr2-dependent signaling plays an important role in breast cancer growth and metastasis.
20540789In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma.
19409696In search for a better understanding of the role of cellular mediators in the progression of cancer, we investigated the effect of pro-inflammatory cytokines IL-1, IL-6, TNF-alpha and IFN-gamma on the regulation of expression of chemokine receptors CXCR4, CXCR2, CX3CR1, CCR9, and CCR5 in the human breast cancer cell line MCF-7.
17949231In conclusion, IL-8 -251T/A polymorphism is associated with development of invasive ductal carcinoma type of breast cancer while CXCR2 +1208C/T polymorphism may affect the disease progression.
22789011Immunohistochemical analysis of human breast tumor samples also confirmed the importance of the hPTTG1/CXCR2 axis in promoting breast cancer metastasis.
17949231IL-8 -251T/A polymorphism and the CXCR2 +1208 C/T polymorphism have a role in breast cancer susceptibility.
21035946Here, we report that targeting CXCR2 and CXCR1 activity using orally active small molecule antagonist (SCH-527123, SCH-479833) inhibits human colon cancer liver metastasis mediated by decreased neovascularization and enhanced malignant cell apoptosis.
22617157Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis.
29383101Here we identify that Ly6GmiLy6CloCD11b+CXCR2+ subpopulation (named CXCR2+ MDSCs) are predominately expanded and recruited in systemic and local tumor microenvironment during breast cancer progression and metastasis.
29383101Furthermore, CXCR2+ MDSCs induce epithelial mesenchymal transition (EMT) of breast cancer cells via IL-6.
28964785Further study suggested that AKT1 and cyclooxygenase-2 (COX2; PTGS2) might mediate the CXCR2 signaling to inversely control the breast cancer metastasis and chemoresistance through the regulation of EMT, apoptosis, and senescence.
20540789Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis.
21042742Expression of CXCR2 mRNA was detectable in all ten colon cancer cell lines examined, whereas expression of GROα mRNA was detectable in six.
28964785CXCR2 promoted anti-apoptosis, anti-senescence, and epithelial-to-mesenchymal transition (EMT) of breast cancer cells, leading to the enhanced metastasis and chemoresistance.
30233217CXCR2 is involved in breast cancer metastasis, treatment resistance, and recurrence and has positive cross-talk with known breast CSC protein markers.
30233217CXCR2 expression decreased in estrogen receptor-negative or HER2-negative breast cancer, but not progesterone receptor-negative counterparts.
22274915CXC-chemokine receptor type 2 (CXCR2) was reported to play critical roles in angiogenesis, tumorigenesis, and metastasis of several cancers such as colon cancer, melanoma, lung cancer, and so on.
22368515CONCLUSIONS: Together, these results suggest that CXCR2 may play a critical role in breast cancer invasion and metastasis.
20540789CONCLUSION: Our results indicated that the polymorphisms in IL-8 and CXCR2 genes are associated with increased breast cancer risk, as well as disease progress, supporting our hypothesis for IL-8 and ELR+CXC chemokine receptor (CXCR2) involvement in breast cancer pathogenesis.
23149820Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity.
29383101Besides, CXCR2+ MDSCs promote breast cancer growth and metastasis to lung and/or lymph node in vivo.
28964785All these data suggest that CXCR2 promotes breast cancer metastasis and chemoresistance via suppressing AKT1 and activating COX2.
22674296After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk.
31562303Additional studies using CXCL5 recombinant protein suggest that CXCL5 is sufficient to promote breast cancer cell proliferation and colonization in bone, while inhibition of its receptor CXCR2 with an antagonist blocks proliferation of metastatic cancer cells.

Wordcloud
To generate a word cloud, a large number of abstracts for CXCR2 are retrieved and analysed for frequently occurring words. Words that are common and non-informative, such as ‘the’, ’and’, ‘this’ etc. (also called stop words), are removed from the word clouds before visualisation. All terms in the word cloud are hyperlinked to PubMed which means that if you click on a term, the corresponding search page in PubMed is opened with that search term combined with the CXCR2 term.

Replacing Western Tumor Specific D199V SSP25 CXCL1 HEK293 Schumacher Elevated Proline Myeloid According Neutrophils UNLABELLED Treatment Matrigel SCH527123 EC9706 D199N CXCR7 GROalpha ApcMin Human NADPH GTPase Lewis Groalpha DESIGN SB225002 Chemokines CXCR4 CXCR2Liver NSCLC Blocking HIMEC CXCL5 Immunohistochemical STAT3 Cxcr2 Infiltration HepG2 Neutrophil Chemokine PP2Ac CXCR1 PKCalpha Silencing Intratumoral Angiotensin Rab11a Liver CXCL10 CXCR2 CXCL8 CXCL2 Overexpression Specifically Recovery Interleukin

Statements
The following section contains a list of sentences that contain the term CXCR2 or one of its synonyms. The sentences are ordered based on the abstracts from which they were retrieved. The highlighted link in the first column is linked to the abstract in PubMed. The search button in the top right can be used to only show sentences with a particular additional keyword.

PMIDNRSENT FACT
28481874 5 CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity.
25682075 1 CXCR2 interacts with a wide range of chemokines and CXCR2 antagonists may have therapeutic value for treatment-resistant metastatic carcinomas.
25682075 2 We aimed to explore regulation of activity of CXCR2 and its ligand, MIP-2, in metastatic breast carcinoma.
25682075 3 We used mouse breast carcinoma cells metastasize to brain (4TBM), liver (4TLM), and heart (4THM) and explored the extra- and intracellular mechanisms effecting MIP-2 secretion using CXCR2 antagonist and inhibitors of downstream signaling molecules.
25682075 4 Specifically, metastatic cells selectively express CXCR2 only, and not CXCR1 and attenuating CXCR2 activity with SB225002 increased MIP-2 secretion.
25682075 5 Attenuating CXCR2 activity with SB225002, otherwise suppressed proliferation of 4THM and 4TBM cells.
25682075 6 Surprisingly, CXCR2 expression was low in 4TLM cells demonstrating that liver metastatic cells might be resistant to the anti-tumoral effects of CXCR2 antagonists.
25682075 7 Our results demonstrated that resistance to anti-proliferative effects of CXCR2 may also arise from feedback increases in MIP-2 secretion.
20018298 9 Furthermore, the protein level of CXCR2 was relevant to TNM staging.
20018298 8 The expression levels of CXCR2 mRNA and protein were correlated with intrahepatic metastasis (P < 0.
27648130 10 Besides, silencing of CXCR2 and CXCR7 significantly reduced tumor growth in vivo, and associated with clinicopathological features and progression.
27648130 11 Silencing of CXCR2 and CXCR7 protects against EC by inhibiting cell growth and chemotaxis, and inducing apoptosis though ERK1/2 pathways.
11278485 8 We postulate that this interaction results from direct binding of the regulatory subunit A (PR65) of PP2A to the carboxyl terminus of CXCR2 after receptor sequestration and internalization.
11278485 1 In the present study, we demonstrate that the carboxyl terminus of CXCR2 physically interacts with the PP2A core enzyme, a dimer formed by PP2Ac and PR65, but not with the PP2Ac monomer, suggesting direct interaction of the receptor with PR65.
11278485 3 CXCR2 co-immunoprecipitates with the PP2A core enzyme in HEK293 cells and in human neutrophils.
11278485 2 The integrity of a sequence motif in the C terminus of CXCR2, KFRHGL, which is conserved in all CC and CXC chemokine receptors, is required for the receptor binding to the PP2A core enzyme.
11278485 5 The dephosphorylation of CXCR2 is reversed by treatment of the cells with okadaic acid.
11278485 4 CXCR2 (331T), which has previously been shown to undergo internalization in HEK293 cells, binds to an almost equal amount of the PP2A core enzyme in comparison with the wild-type CXCR2, suggesting that the interaction of the receptor with PP2A is phosphorylation-independent.
11278485 7 Taken together, these data indicate that PP2A is involved in the dephosphorylation of CXCR2.
11278485 6 Moreover, pretreatment of the cells with okadaic acid increases basal phosphorylation of CXCR2 and attenuates CXCR2-mediated calcium mobilization and chemotaxis.
20018298 3 In this study, we aimed to investigate the association between CXCR2 expression and the biocharacteristics of HCC, and determine whether the expression of CXCR2 was related to the tumorigenesis and progression.
20018298 10 The protein level of CXCR2 in stage III-IV was remarkably higher than in stage I-II (P < 0.
22368515 3 We hypothesize that the chemokine receptor, CXCR2, mediates tumor cell invasion and migration and promotes metastasis in breast cancer.
22368515 2 The functional role of CXCR2 in the metastatic phenotype of breast cancer still remains unclear.
22961770 1 CXCR2 is constitutively expressed on both neutrophils and hepatocytes; however, the cell-specific roles of this receptor are unknown.
23869868 1 Chemokine receptor CXCR2 was previously reported to mediate replicative and oncogene-induced senescence in a DDR and p53-dependent manner.
23869868 3 Unexpectedly, we found that the upregulation of CXCR2 depends on the function of p53.
23869868 2 Here, we report that CXCR2 is upregulated in various types of cells in response to genotoxic or oxidative stress.
23869868 5 We identified a p53-binding site in the CXCR2 promoter that responds to changes in p53 functional status.
23869868 4 Like other p53 target genes such as p21, CXCR2 is transactivated by p53.
23869868 7 While the senescence-associated secretory phenotype (SASP) exhibits a kinetics that is distinct from that of CXCR2 expression and does not require p53, it reinforces senescence.
23869868 6 Thus, CXCR2 may act downstream of p53.
25484047 7 The scFvs from the CXCR2 specific phage clones were sequenced and converted into monoclonal antibodies.
23869868 8 We further showed that the cellular senescence caused by CXCR2 upregulation is mediated by p38 activation.
25484047 5 These peptides were used as antigens to probe an antibody fragment phage display library to obtain subpopulations binding to the IL-8 binding site of CXCR2.
25484047 4 The IL-8 binding site of CXCR2 was identified by screening peptide libraries with the IL-8 ligand, and then reconstructed as soluble synthetic peptides.
25484047 3 Here we present a combination of techniques that improve the discovery of functional monoclonal antibodies against the native CXCR2 receptor.
25484047 2 SUMMARY: The CXC chemokine receptor-2 (CXCR2) is a member of the large 'family A' of G-protein-coupled-receptors and is overexpressed in various types of cancer cells.
25484047 1 CONCLUSION: The combination of techniques provides a successful strategic approach for the development of functional monoclonal antibodies against CXCR2 in a relatively small campaign.
22961770 6 Myeloid expression of CXCR2 directly regulated CXC chemokine expression levels after hepatic I/R, such that mice lacking myeloid CXCR2 had markedly increased chemokine expression, compared with mice expressing CXCR2 on myeloid cells.
22368515 5 The effects of CXCR2 downregulation on tumor growth, invasion and metastatic potential were analyzed in vitro and in vivo.
22368515 4 The objective of this study is to investigate the potential role of CXCR2 in the metastatic phenotype of mouse mammary tumor cells.
27324095 3 METHODS: CXCR2 expression levels in newly delivered placentas from 38 pregnant women with PE and 21 healthy pregnant women were detected using quantitative real-time PCR, immunohistochemistry and Western blot assays.
27324095 2 It is unclear what impact CXCR2 may have on Preeclampsia (PE), a pregnancy-specific disease, which is related to insufficient trophoblast invasion.
27324095 1 INTRODUCTION: CXCR2, the receptor of the CXC chemokines, plays a critical role in cell migration and invasion in many types of cancer.
31516616 3 Higher levels of CXCR1, CXCR2 and IL-8 were associated with advanced tumor stage and increased risk of lymph node or distant metastasis.
31516616 4 Immunohistochemistry showed that the IL-8, CXCR1 and CXCR2 proteins were expressed in the cytoplasm of hepatoma cells at higher intensities than those of normal controls (P<0.
27324095 6 DISCUSSION: Our results suggest that the decreased CXCR2 may contribute to the development of preeclampsia through impairing trophoblast invasion by down-regulating MMP-2 and MMP-9 via the Akt signaling pathway.
27324095 5 The invasive abilities of the two trophoblast cell lines were significantly inhibited when CXCR2 was silenced, but that CXCR2 overexpression promoted trophoblast cells invasion.
27324095 4 RESULTS: CXCR2 mRNA and protein expression levels were significantly decreased in preeclamptic placentas than normal control.
31516616 8 Pretreatment of the cells with anti-CXCR1 or anti-CXCR2 (5 µM) for 30 min markedly inhibited IL-8-directed cell migration.
31516616 9 Taken together, these results indicated that IL-8 promotes liver cancer cell migration via CXCR1 and CXCR2 and that targeting the CXCR1/2 may be a potential strategy for liver cancer treatment.
20610741 4 Here, we show that the actions of CXCR2 on nonhematopoietic cells unexpectedly delay myelin repair.
20610741 5 Bone marrow chimeric mice (Cxcr2(+/-)-->Cxcr2(-/-) and Cxcr2(+/-)-->Cxcr2(+/+)) were subjected to two distinct models of myelin injury.
20610741 6 In all cases, myelin repair was more efficient in Cxcr2(+/-)-->Cxcr2(-/-) animals.
20610741 7 Oligodendrocyte progenitor cells (OPCs) in demyelinated lesions of Cxcr2(+/-)-->Cxcr2(-/-) mice proliferated earlier and more vigorously than in tissues from Cxcr2(+/-)--> Cxcr2(+/+) animals.
20610741 1 CXCR2-positive neutrophils facilitate inflammatory demyelination in demyelination models such as experimental autoimmune encephalomyelitis (EAE) and cuprizone intoxication.
26497045 8 CXCR2 might be a promising therapeutic target of postoperative adjuvant treatment.
20610741 3 These results left the cellular target of the CXCR2 antagonist uncertain and did not clarify whether CXCR2 blockade prevented demyelination or promoted remyelination.
26497045 6 CXCR2 expression was an independent prognostic factor for OS (p = 0.
26497045 7 CONCLUSION: Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients.
26497045 4 RESULTS: CXCR2 expression was mainly located in the cytoplasm of gastric carcinoma cells.
26497045 5 High CXCR2 expression was associated with poor tumor differentiation (p = 0.
26497045 2 The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection.
20610741 9 Our results suggest that CXCR2 inactivation permits optimal spatiotemporal positioning of OPCs in demyelinating lesions to receive local proliferative and differentiating signals.
26497045 1 BACKGROUND: CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells.
10747307 8 CONCLUSIONS: The expression of CXCR2 by normal neuroendocrine cells and neoplastic counterparts that have retained phenotypic features of this differentiation program suggests that chemokines may play an important role in functions that are characteristic of this cell type.
24582495 8 Cell proliferation, migration, and invasion were significantly suppressed by both CXCR2 siRNA and SB225002 compared with the control group.
24582495 6 The expression of CXCR2 in ICC was determined by immunohistochemical staining of 34 ICC specimens.
24582495 7 CXCR2 siRNA treatment significantly suppressed CXCR2 expression in both RBE and SSP25.
24582495 4 CXCR2 small interfering RNA (siRNA) and an antagonist (SB225002) were used to block CXCR2.
10747307 3 OBJECTIVE: To determine the expression of CXCR2 by cells of the neuroendocrine system.
24582495 2 In this study, we investigated the suppressive effect of ICC growth by blocking CXCR2.
24582495 3 MATERIAL AND METHODS: The role of CXCR2 was estimated using the human ICC cell lines, RBE and SSP25.
10747307 6 Neuroendocrine neoplasms that demonstrated high-level CXCR2 expression included (1) primary carcinoids localized to the stomach, small bowel, colon, appendix, fallopian tube, ovary, and lung; (2) atypical carcinoids of the lung; (3) metastatic carcinoids; (4) pituitary adenomas; (5) pheochromocytomas; and (6) medullary carcinomas of the thyroid.
10747307 7 Small cell lung carcinomas, large cell neuroendocrine carcinomas of the lung, small cell carcinoma of the cervix, Merkel cell carcinomas, neuroblastomas, and malignant melanomas lacked evidence of CXCR2 expression.
23868943 2 Similarly, CXCR2 displays opposing effects in resident versus circulating cells.
23868943 3 Blocking MIF increased infarction size and impaired cardiac function in wt/wt and wt/CXCR2(-/-) mice but ameliorated functional parameters in Cxcr2(-/-)/wt mice, as analyzed by echocardiography and Langendorff perfusion.
23868943 1 As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2.
23868943 6 Furthermore, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner.
23868943 7 CONCLUSIONS: The compartmentalized and opposing effects of MIF after myocardial ischemia and reperfusion are largely mediated by CXCR2.
23868943 4 Neutrophil infiltration and angiogenesis were unaltered by MIF blockade or Cxcr2 deficiency.
23868943 5 Monocyte infiltration was blunted in wt/Cxcr2(-/-) mice and reduced by MIF blockade in wt/wt and Cxcr2(-/-)/wt mice.
20018298 1 BACKGROUND: An ELR+ CXC chemokine receptor, CXCR2, was recently reported to be involved in tumorigenesis and development.
23868943 8 Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CXCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function.
20018298 2 However, the role of CXCR2 in hepatocellular carcinoma (HCC) is poorly understood.
20018298 5 RESULTS: Expression levels of CXCR2 were significantly increased in HCC compared with adjacent and normal liver tissues (P < 0.
20018298 4 CXCR2 mRNA and protein expressions were examined using semiquantitative reverse transcription-PCR and Western blot.
20018298 7 Also, there was no relationship between CXCR2 mRNA expression and TNM staging.
20018298 6 The results showed that CXCR2 mRNA and protein expression levels were not related to age, gender, AFP levels, tumor capsule, or tumor size.
22961770 3 Interestingly, Kupffer cells from all chimeras lacked CXCR2 expression.
22961770 2 These tools allowed us to assess the contributions of myeloid and hepatocyte CXCR2 in the recovery of the liver after I/R injury.
22368515 1 Previous studies have shown that CXCR2 expression is upregulated in malignant breast cancer tissues but not in benign ductal epithelial samples.
22961770 7 CONCLUSION: The data suggest that CXCR2 on myeloid cells is the predominant regulator of liver recovery and regeneration after I/R injury, whereas hepatocyte CXCR2 plays a minor, secondary role.
22368515 6 RESULTS: We demonstrated knock down of CXCR2 in Cl66 and 4T1 cells (Cl66-shCXCR2 and 4T1-shCXCR2) cells by reverse transcriptase polymerase chain reaction (RT-PCR) at the transcriptional level and by immunohistochemistry at the protein level.
22961770 5 CXCR2(Hep+/My-) mice had enhanced liver recovery, with hepatocyte proliferation similar to CXCR2(Hep-/My-) mice.
22961770 4 CXCR2(Hep+/My+) mice showed the least amount of liver recovery and hepatocyte proliferation, whereas CXCR2(Hep-/My-) mice had the greatest liver recovery and hepatocyte proliferation.
22368515 9 CONCLUSIONS: Together, these results suggest that CXCR2 may play a critical role in breast cancer invasion and metastasis.
22368515 8 CXCR2 downregulation significantly inhibited tumor cell metastasis.
14500678 4 The anti-CXCR2 Ab treatment delayed, but did not completely inhibit, the recruitment of leukocytes, specifically neutrophils, into the peritoneal cavity.
14500678 5 Peritoneal macrophages from anti-CXCR2 Ab-treated mice exhibited markedly increased RNA and protein levels of several key proinflammatory cytokines and chemokines.
14500678 6 CXCR2(-/-) mice had higher resting and CLP-induced levels of peritoneal CXCL10 compared with CXCR2(+/+) mice.
14500678 7 Anti-CXCL10 treatment in CXCR2(-/-) mice negated the protective effect associated with the absence of CXCR2.
14500678 1 The loss of CXCR2 expression by neutrophils is a well-described, but poorly understood, consequence of clinical sepsis.
14500678 2 CXCR2-specific polyclonal Ab.
14500678 3 Furthermore, mice deficient in CXCR2 (CXCR2(-/-)) were significantly protected against CLP-induced mortality compared with control (CXCR2(+/+)) mice.
14500678 8 In summary, these data demonstrate that the absence of CXCR2 protects mice from septic injury potentially by delaying inflammatory cell recruitment and enhancing CXCL10 expression in the peritoneum.
12496258 8 Supported by the notion that malignant colonic epithelial cells overexpress IL-8, CXCR2 blockade may be a novel target for anti-angiogenic therapy in colorectal adenocarcinoma.
10747307 5 RESULTS: Immunohistochemical analysis revealed high-level expression of CXCR2 by cells in the pituitary, adrenal medulla, pancreatic islets, thyroid C cells, scattered Kulchitsky cells in the bronchi, and counterpart neuroendocrine cells in the stomach, small bowel, colon, and appendix.
12496258 1 The chemokine interleukin 8 (IL-8; CXCL8) exerts potent angiogenic properties on endothelial cells through interaction with its cognate receptors CXCR1 and CXCR2.
12496258 2 As CXCR1 and CXCR2 expression is differentially regulated in tissue-specific endothelial cells and effects of IL-8 on intestinal endothelial cells are not defined, we characterized the potential IL-8-induced angiogenic mechanisms in primary cultures of human intestinal microvascular endothelial cells (HIMEC) and IL-8 receptor expression in human intestinal microvessels.
12496258 3 CXCR1 and CXCR2 expression on HIMEC were defined using reverse transcriptase-PCR, immunohistochemistry, flow cytometry, and Western blot analysis.
12496258 4 HIMEC express CXCR2, but not CXCR1.
12496258 5 Neutralizing antibodies to CXCR2 diminished IL-8-induced chemotaxis and stress fiber assembly.
12496258 6 IL-8 elicits angiogenic responses in microvascular endothelial cells isolated from human intestine by engaging CXCR2.
12496258 7 We confirmed tissue expression of CXCR2 in human intestinal microvessels.
23972657 8 As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.
23972657 9 CONCLUSION: Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients.
23972657 2 CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells.
23972657 3 To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear.
23972657 1 BACKGROUND: CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells.
23972657 6 RESULTS: Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively.
23972657 7 CXCL-8(+)/CXCR-2(+) group compared with the other group.
23972657 4 We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry.
23972657 5 The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed.
14978086 2 We hypothesized that CXCR2 mediates the proangiogenic effects of ELR(+) CXC chemokines during tumorigenesis.
14978086 3 Next, we found that LLC primary tumors were significantly reduced in growth in CXCR2(-/-) mice.
14978086 1 ELR(+) CXC chemokines share a common chemokine receptor, CXCR2.
14978086 6 These findings were further confirmed in CXCR2(+/+) mice using specific neutralizing Abs to CXCR2.
25022956 8 In contrast, overexpression of CXCR1 and CXCR2 proteins promoted tumor cell migration and invasion.
14978086 4 Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2(-/-) mice.
25022956 4 RESULTS: CXCR1, CXCR2, and MMP9 were expressed in 61.
25022956 5 Moreover, CXCR1 and CXCR2 expression was associated with tumor differentiations, advanced clinical stages, lymph node, and distant metastasis of gastric cancer.
25022956 6 Similarly, MMP9 expression was associated with CXCR1 and CXCR2.
14978086 5 Morphometric analysis of the primary tumors in CXCR2(-/-) mice demonstrated increased necrosis and reduced vascular density.
25022956 1 BACKGROUND: CXCR1 and CXCR2, cell surface receptors of interleukin-8, regulate cell migration and alteration of their expression has been associated with poor prognosis of various cancers.
25022956 2 MATERIALS AND METHODS: A total of 172 cases of gastric cancer tissue specimens were collected for immunohistochemical analysis of CXCR1, CXCR2, and MMP9 expression.
25022956 3 Expression of CXCR1 and CXCR2 proteins was knocked in or down using their cDNA and shRNA, respectively, in gastric cancer cell lines to assess the changed cell phenotypes and gene expression.
25990934 10 CONCLUSIONS: CXCL1 secreted by astrocytes and endothelial CXCR2 play essential roles in cerebral endothelial activation and subsequent leukocyte recruitment during neuroinflammation.
25022956 10 Conversely, upregulation of CXCR1 or CXCR2 promoted expression of Ets-1, SRC-1, JNK, and c-Jun proteins and phosphorylated JNK, c-Jun and Erk1/2.
25022956 11 CONCLUSIONS: These findings suggest that CXCR1 and CXCR2 play an important role in gastric cancer progression.
27678262 1 Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases.
27678262 3 Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry.
27678262 2 However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown.
27678262 5 Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
27678262 4 CONCLUSIONS: Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction.
26586954 10 Therefore, CXCR2 may serve as a potential therapeutic target for the recurrence and migration of gliomas.
20505188 4 Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-kappaB, and tumor growth.
20505188 5 Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples.
20505188 6 RESULTS: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice.
20505188 7 CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1.
20505188 1 PURPOSE: Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive.
20505188 2 Here, we investigated the role of CXCR2 in human ovarian cancer.
20505188 3 EXPERIMENTAL DESIGN: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3.
20505188 8 CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2.
20505188 9 Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.
9726994 6 Taken together, these results suggest that CXCR1 and CXCR2 bind IL-8 to produce a group of equipotent responses, but their ability to generate other signals, including receptor internalization, cross-desensitization, and phospholipase D activation, are very different.
9726994 7 The latter phenomena apparently require prolonged receptor activation, which in the case of CXCR2 is precluded by rapid receptor phosphorylation and internalization.
9726994 4 Truncation of the cytoplasmic tail of CXCR2 (331T) prolonged its signaling relative to CXCR2, increased its resistance to internalization, and induced phospholipase D activation.
9726994 5 CXCR2 and the mutant 331T induced phospholipase C beta3 phosphorylation to an extent equivalent to that of CXCR1.
9726994 2 To investigate this phenomenon, CXCR2 was stably expressed in RBL-2H3 cells and mediated phosphoinositide hydrolysis, Ca2+ mobilization, chemotaxis, and secretion.
9726994 3 However, neither C5aR nor FR was cross-phosphorylated or cross-desensitized by CXCR2 activation, although CXCR1 did mediate this process.
9726994 1 Neutrophils and transfected RBL-2H3 cells were used to investigate the mechanism of cross-regulation of the human interleukin-8 (IL-8) receptors CXCR1 and CXCR2 by chemoattractants.
25950520 5 Importantly, pharmacological inhibition of CXCR2 in wild-type mice replicated the protection seen in Cxcr2(-/-) mice in acute and chronic models of pancreatitis.
25950520 4 Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non-neutrophils contributes to the development of chronic pancreatitis.
25950520 7 Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage.
25950520 6 Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2.
25950520 1 The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild-type and Cxcr2(-/-) mice.
25950520 3 The pancreata of Cxcr2(-/-) mice were also substantially protected from damage during chronic pancreatitis.
25950520 2 Strikingly, Cxcr2(-/-) mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells.
25950520 8 CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis.
12888558 1 The CXCR2 is a GPCR that is activated, among the others, by the chemokines CXCL8 (interleukin-8) and CXCL2 (growth-related gene product beta) to induce cell chemotaxis.
12888558 2 We have investigated the oligomerization of CXCR2 receptors expressed in human embryonic kidney cells and generated a series of truncated mutants to determine whether they could negatively regulate the wild-type (wt) receptor functions.
12888558 3 CXCR2 receptor oligomerization was also studied by coimmunoprecipitation of green fluorescent protein- and V5-tagged CXCR2.
12888558 4 Truncated CXCR2 receptors retained their ability to form oligomers only if the region between the amino acids Ala-106 and Lys-163 was present.
12888558 5 In contrast, all of the deletion mutants analyzed were able to form heterodimers with the wt CXCR2 receptor, albeit with different efficiency, competing for wt/wt dimer formation.
12888558 6 The truncated CXCR2 mutants were not functional and, when coexpressed with wt CXCR2, interfered with receptor functions, impairing cell signaling and chemotaxis.
12888558 7 When CXCR2 was expressed with the AMPA-type glutamate receptor GluR1, CXCR2 dimerization was again impaired in a dose-dependent way, and receptor functions were prejudiced.
12888558 8 In contrast, CXCR1, a chemokine receptor that shares many similarities with CXCR2, did not dimerize alone or with CXCR2 and when coexpressed with CXCR2 did not impair receptor signaling and chemotaxis.
12888558 9 The formation of CXCR2 dimers was also confirmed in cerebellar neuron cells.
22922255 7 Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation.
28845733 5 Chromatin immunoprecipitation experiments demonstrated TBI-enhanced association of the CXCR2 promoter with acetylated-H3K9 histone protein that was also reversible using anacardic acid.
28845733 4 Most of the spinal CXCR2 appeared to be expressed by spinal cord neurons.
28845733 3 The same drug was able to prevent the upregulation of CXCR2 after TBI, but did not affect the spinal expression of other pain mediators.
28845733 2 The spinal levels of several pain-related mediators including CXCL1, an endogenous ligand for CXCR2, as well as brain-derived neurotrophic factor and prodynorphin were measured by enzyme-linked immunosorbent assay.
28845733 1 The expression of the CXCR2 receptor was accomplished using real-time PCR, immunohistochemistry, and Western blotting, while epigenetic regulation was assessed using chromatin immunoprecipitation assay.
31243125 2 Generation of Plp-Cre-ER(T)::Cxcr2flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen.
31243125 3 Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice.
31243125 1 CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia.
31243125 6 These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases.
31243125 4 To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen.
31243125 5 Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination.
25022956 7 In vitro study showed that levels of CXCR1 and CXCR2 proteins were associated with the capacity of gastric cancer cell migration, while knockdown of their expression inhibited gastric cancer cell migration and invasion abilities in vitro.
22231733 1 II-IV) were investigated for the association of SOCS-3 and CXCR2 expression with clinicopathologic and morphometric microvascular characteristics, vascular endothelial growth factor (VEGF), IL-8 and p-STAT-3 expression and patient survival.
22231733 2 SOCS-3, p-STAT-3 and CXCR2 protein levels were also quantified by Western immunoblotting in six cases, and the protein levels of SOCS-3 and CXCR2 were correlated with the immunohistochemical expression of the respective proteins.
22231733 3 All CXCR2-positive cases by Western immunoblotting displayed increased peripheral IL-8 secretion levels.
22231733 4 Treatment of primary glioblastoma cell cultures with exogenous IL-8 enhanced proliferation, and this effect was inhibited by treatment with a neutralizing anti-CXCR2 antibody.
22231733 5 SOCS-3 and CXCR2 were expressed by neoplastic astrocytes in 92.
22231733 6 VEGF expression and microvessel density, CXCR2 and IL-8 levels were interrelated.
22231733 7 In univariate survival analysis, increased SOCS-3 expression and the presence of CXCR2 adversely affected survival, whereas in multivariate analysis, only CXCR2 remained significant.
22231733 8 The prognostic significance of CXCR2 was validated in an independent set of 63 patients.
22231733 9 Our data implicate IL-8/CXCR2 signaling pathway in the progression and regulation of angiogenesis in astrocytomas and provide a rationale for CXCR2 therapeutic exploitation in these tumors.
9195914 8 The selective antagonists described may be used in future studies on IL-8 receptor signaling to define distinct steps leading to various functional responses induced in neutrophils via CXCR1 and CXCR2.
9195914 2 We have now examined the effect of NH2-terminally modified analogs of IL-8, GROalpha, and PF4 on CXCR1 and CXCR2 independently.
9195914 3 Using stable Jurkat transfectants expressing either CXCR1 or CXCR2, it was shown that analogs derived from IL-8 bound both IL-8 receptors with similar affinity and could block IL-8-induced Ca2+ mobilization.
9195914 1 Human neutrophils express two interleukin (IL)-8 receptors, CXC chemokine receptor (CXCR) 1 and CXCR2.
9195914 6 Thus (R)GROalpha and (R)PF4 inhibited only the GROalpha but not the IL-8-stimulated elastase release, and these two analogs had no effect on IL-8-elicited superoxide generation, a response that is mediated by CXCR1 but not by CXCR2.
9195914 7 These results show that CXCR2 selective receptor antagonists can be generated based upon the secondary binding determinants of GROalpha and PF4.
9195914 4 By contrast, analogs of GROalpha and PF4, (R)GROalpha and (R)PF4, bound only CXCR2 with high affinity and blocked Ca2+ mobilization induced only via CXCR2.
9195914 5 The differential effect on CXCR1 and CXCR2 was also demonstrated in studies with isolated neutrophils.
24953191 1 CXCR2, the receptor of CXC chemokines, has been reported to be involved in invasion and metastasis in multiple types of malignancy.
24953191 3 Then, we established stable OSCC cell lines with interference of CXCR2 and observed the effect of CXCR2 knockdown on cell proliferation, migration, invasion, and morphological changes in vitro and in vivo.
24953191 2 However, the accurate role of CXCR2 in OSCC has been little noticed.
24953191 5 CXCR2 silencing markedly inhibited migration and invasion of OSCC cells in vitro and in vivo.
24953191 4 RESULTS: CXCR2 was positively expressed in 55.
24953191 7 However, CXCR2 silencing showed no effect on proliferation of OSCC cells in vitro and in vivo.
24953191 6 Moreover, CXCR2 silencing led to morphological changes and decreased lamellipodial structures in OSCC cells.
25484047 8 The obtained antibodies bound specifically to CXCR2 expressing cells and inhibited the IL-8 and Gro-α induced ß-arrestin recruitment with IC50 values of 0.
23869868 9 Our results thus demonstrate CXCR2 as a critical mediator of cellular senescence downstream of p53 in response to DNA damage.
25484047 6 Further enrichment of the phage population was achieved by an additional selection round with CXCR2 overexpressing cells as a different antigen source.
18688883 5 SB225002 treatment increased hepatocyte proliferation and regeneration in a manner identical to that observed in CXCR2(-/-) mice.
18688883 4 Hepatocyte proliferation and regeneration was accelerated in CXCR2(-/-) mice compared with wild-type mice.
18688883 7 CONCLUSION: Our data suggest that hepatocyte CXCR2 regulates proliferation and regeneration after I/R injury and reveal important differences in the role of this receptor in liver regeneration and repair induced under different conditions that may be related to ligand concentration.
18688883 6 These effects were absent in hepatocytes from CXCR2(-/-) mice.
18688883 1 Wild-type and CXCR2(-/-) mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 96 hours of reperfusion.
14978086 7 The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR(+) CXC chemokines in a preclinical model of lung cancer.
18688883 3 Early neutrophil recruitment (12 hours) was diminished in CXCR2(-/-) mice, but within 24 hours it was the same as that of wild-type mice.
18688883 2 CXCR2(-/-) mice had significantly less liver injury at all reperfusion times compared with wild-type mice.
23204236 8 The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.
23204236 5 Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo.
23204236 4 Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines.
23204236 7 CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis, and RAS pathway activation.
23204236 6 In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis.
23204236 1 CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis.
23204236 3 Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas.
23204236 2 Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells.
20540789 5 METHODS: We used the allele-specific polymerase chain reaction to characterize the variation of IL-8 and CXCR2 for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects.
26586954 1 CXCR2), a member of the G-protein-coupled receptor family, is an interleukin-8 receptor and results in the activation of neutrophils.
26586954 2 To date, CXCR2 has been identified with many cell events, including inflammation, neovascularization, metastasis, and cell carcinogenesis.
26586954 3 This study aimed to investigate alterations in the expression of CXCR2 in patients with brain gliomas and relationships with pathological grades and clinicopathological characteristics.
26586954 4 Western blotting was used to evaluate CXCR2 protein levels with fresh tissues derived from glioma cases or controls.
26586954 5 Correlations between CXCR2 expression and clinicopathological characteristics were analyzed using SPSS software.
26586954 6 The results showed high-grade gliomas with high CXCR2 expression as compared with normal tissues.
26586954 7 The expression of CXCR2 was significantly related to high grades and recurrence of tumor but not to age or sex.
26586954 8 During an in vitro wound healing assay, U251 migration was reduced when the CXCR2-specific inhibitor SB225002 was applied.
26586954 9 Our results suggested that the high expression of CXCR2 in gliomas was closely correlated to the degree of malignancy and recurrence and that CXCR2 inhibition decreased the migration of glioma cells.
20599927 8 These studies indicate that N-alpha-PGP is not a ligand of CXCR1 or CXCR2.
20599927 4 PGP was not able to displace the radioligand [(125)I]CXCL8 from CXCR1 and CXCR2 expressing HEK293T cells or neutrophils.
20599927 5 In addition, N-alpha-PGP did not displace the radioligand [(3)H]-SB265610, a CXCR2 antagonist, from CXCR2 expressing cells.
20599927 6 Furthermore, N-alpha-PGP was not able to activate G protein signalling in cells expressing CXCR1 and CXCR2.
20599927 7 PGP was also not able to recruit beta-arrestin2, an intracellular scaffolding protein involved in G protein-independent signalling, in cells expressing CXCR2.
20599927 1 Neutrophils transmigrate from the blood into inflamed tissue via the interaction of chemokines produced in this tissue with chemokine receptors, such as CXCR1 and CXCR2, that are expressed on the membranes of neutrophils.
20599927 2 PGP exerts its effect via CXCR1 and CXCR2.
20599927 3 In this study, we show that N-alpha-PGP, in contrast to CXCL8, does not directly activate or interact with CXCR1 or CXCR2.
31516616 1 However, the expression and functional roles of IL-8 and its receptors, CXC chemokine receptor (CXCR) 1 and CXCR2 in the progression of liver cancer remain to be fully elucidated.
31516616 2 In the present study, it was shown that the mRNA levels of IL-8, CXCR1 and CXCR2 were increased in peripheral blood mononuclear cells from patients with liver cancer compared with those from patients with cirrhosis or normal controls (P<0.
31516616 5 The semi-quantitative analysis revealed that the relative mean density of hepatic IL-8, CXCR1 and CXCR2 staining in liver cancer was significantly increased compared with that in normal liver tissues (P<0.
31516616 6 CXCR2 (r=0.
31604030 1 SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibitor.
31516616 7 The mRNA levels of CXCR1 and CXCR2 gradually increased with elevated expression of IL-8 in liver cancer.
31604030 2 CXCR2 -/- mice showed significantly less neutrophil accumulation in those injured area.
31604030 3 CXCR2 Liver+/Myeloid+and CXCR2Liver-/Myeloid-mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively.
31604030 5 In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation.
24376747 11 Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-κB activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.
24376747 10 Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-κB site.
31604030 6 CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.
22922255 8 CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation.
22922255 9 Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.
22922255 1 The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development.
22922255 2 However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context.
22922255 3 Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors.
22922255 4 CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models.
22922255 5 Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice.
22922255 6 Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment.
25022956 9 At the gene levels, knockdown of CXCR1 or CXCR2 expression suppressed expression of Ets-1, SRC-1, and JNK proteins and phosphorylated c-Jun and Erk1/2.
19118017 7 Thus, activation of CXCR2 on ras-transformed keratinocytes has both promigratory and protumorigenic functions.
19118017 6 Both migration and activation of ERK and Akt were restored by CXCR2 reconstitution of CXCR2 null keratinocytes.
19118017 5 In vitro, CXCR2 was essential for CXCR2 ligand-stimulated migration of ras-transformed keratinocytes and for ligand activation of the extracellular signal-regulated kinase (ERK) and Akt pathways.
19118017 4 However, ras transformed CXCR2 null keratinocytes formed only small skin tumors in orthotopic skin grafts to CXCR2 intact hosts, whereas transformed wild-type keratinocytes produced large tumors.
19118017 3 Oncogenic ras also induced CXCR2 ligands in keratinocytes genetically ablated for CXCR2.
19118017 2 Ras induction of CXCR2 ligands was mediated by autocrine activation of epidermal growth factor receptor and nuclear factor-kappaB, and potentiated by PKCalpha.
19118017 1 We confirmed that CXCR2 is expressed by keratinocytes and showed that transformation by oncogenic ras (a hallmark of DMBA initiation) or TPA exposure induced all CXCR2 ligands.
28481874 4 Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients.
28481874 9 Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
28481874 8 Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis.
19118017 8 The up-regulation of CXCR2 ligands after initiation by oncogenic ras and promotion with TPA in the mouse skin model provides a mechanism to stimulate migration by both autocrine and paracrine pathways and contribute to tumor development.
25990934 8 Additionally, CXCR2 messenger RNA (mRNA) expression in cerebral endothelial cells but not in microglia or astrocytes was increased following tumor necrosis factor-α (TNF-α) stimulation.
25990934 9 The intravenous injection of the CXCR2 antagonist SB225002 significantly inhibited endothelial activation and leukocyte recruitment to cerebral microvessels.
25990934 2 METHODS: Wild-type (WT), CXCL1(-/-), and CXCR2(-/-) mice each received an intracerebroventricular (i.
25990934 3 To identify the cellular source of functional CXCR2, chimeric mice were generated by transferring bone marrow cells between the WT and CXCR2(-/-) mice.
25990934 1 In this study, we investigated the roles of CXCR2 and CXCL1 in leukocyte recruitment to the CNS using a murine model of neuroinflammation.
25990934 6 Furthermore, the bone marrow transfer experiments demonstrated that CXCR2 expression on CNS-residing cells is essential for cerebral endothelial activation and leukocyte recruitment.
25990934 7 Astrocyte culture conditioned medium significantly increased the expression of VCAM-1 and ICAM-1 in cerebral endothelial cells in a CXCR2-dependent manner.
25990934 4 CXCR2 or CXCL1 deficiency blocked neutrophil infiltration and leukocyte recruitment in the cerebral microvessels.
25990934 5 In the CXCR2(-/-) and CXCL1(-/-) mice, the cerebral endothelial expression of adhesion molecules such as P-selectin and VCAM-1 was dramatically reduced.
20610741 10 Given that CXCR2 exerts dual functions that promote demyelination and decrease remyelination by actions toward hematopoietic cells and nonhematopoietic cells, respectively, our findings identify CXCR2 as a promising drug target for clinical demyelinating disorders.
12442335 3 Analysis of inter-relationships between CXCR1 and CXCR2 during internalization indicated that the exposure of cells that expressed both CXCR1 and CXCR2 to CXCL8 or CXCL6 resulted in decreased levels of CXCR1 internalization as compared to those in cells that expressed only CXCR1.
12442335 2 Elevated levels of internalization were induced by different ELR-expressing CXC chemokines on the chimeric receptor, as compared to wild-type CXCR2.
12442335 1 In this study we investigated the regulation of CXCR1 and CXCR2 intracellular trafficking.
12442335 7 In all, CXCR1 and CXCR2 internalization and recycling are tightly regulated by receptor domains and by actin-related kinases.
12442335 6 The kinase-dependent recycling process required CXCR2 C-terminal phosphorylation sites.
12442335 5 The presence of wortmannin during receptor recycling inhibited CXCR1 and CXCR2 re-expression following CXCL8-induced internalization, and resulted in a marked disruption of the proper organization of actin filaments.
12442335 4 To characterize the role of actin-related components in CXCR1 and CXCR2 trafficking, wortmannin, a potent inhibitor of phosphatidylinositol kinases, was used.
17204468 7 Like CXCR1, B(D199V)A also induced sustained ERK activation and cross-desensitized Ca(2+) mobilization to CCR5 relative to B(D199N) and CXCR2.
17204468 6 D199N) internalized rapidly but migrated as a single phosphorylated form like CXCR1 ( approximately 75 kDa), whereas B(2ECL)A and B(D199V)A showed slow and fast migrating forms like CXCR2 ( approximately 45 and approximately 65 kDa, respectively) but internalized like CXCR1.
17204468 5 Structure modeling of the 2ECL of the receptors also suggested that Asp(199) plays a critical role in stabilizing and modulating CXCR2 rapid internalization relative to CXCR1.
17204468 4 Replacing Asp(199) with Asn (B(D199N)) restored CXCR2 rapid internalization.
17204468 3 Replacing the 2ECL of CXCR2 with that of CXCR1 (B(2ECL)A) or Asp(199) with its CXCR1 valine counterpart (B(D199V)A) delayed CXCR2 internalization similarly to CXCR1.
17204468 2 To determine the structural determinant(s) that modulate receptor internalization, various chimeric and point mutant receptors were generated by progressively exchanging specific domains or amino acids between CXCR1 and CXCR2.
17204468 1 CXCL8 (interleukin-8) interacts with two receptors, CXCR1 and CXCR2, to activate leukocytes.
28845733 6 Taken together, our findings suggested that TBI causes the upregulation of spinal CXCR2 through an epigenetic mechanism ultimately supporting nociceptive sensitization.
20540789 10 CONCLUSION: Our results indicated that the polymorphisms in IL-8 and CXCR2 genes are associated with increased breast cancer risk, as well as disease progress, supporting our hypothesis for IL-8 and ELR+CXC chemokine receptor (CXCR2) involvement in breast cancer pathogenesis.
24376747 5 CXCR2 transfected cells expressed higher levels of its proinflammatory ligands, CXCL1/2 and enhanced more proliferation, migration, invasion and colony formation.
24376747 4 Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells.
24376747 7 Enhanced NF-κB activity in CXCR2 positive cells was reduced by a PI3K/Akt inhibitor rather than an Erk inhibitor.
24376747 6 CXCR2 positive cells also activated more EGFR, which led to higher Akt activation.
24376747 1 CXCR2 expressing ovarian cancers are aggressive with poorer outcomes.
24376747 3 Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector.
24376747 2 We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines.
24376747 9 In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF-κB inhibitor.
24376747 8 CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-κB inhibitor, Bay 11-7082.
22368515 7 We did not observe a significant difference in in vitro cell proliferation between vector control and CXCR2 knock-down Cl66 or 4T1 cells.
12411301 2 CXCR2 was colocalized with Rab5 and Rab11a, which are localized in early and recycling endosomes, respectively, in response to agonist stimulation for a short period of time, suggesting a recycling pathway for the receptor trafficking.
20505188 10 CONCLUSIONS: Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-kappaB, in ovarian cancer.
20505188 11 CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis.
10878382 2 Here we report on the identification and characterization of distinct CXCR-2 glycoforms and their subcellular distribution in neutrophils.
10878382 3 Immunoprecipitation and Western blot analyses of surface-expressed receptors covalently linked to IL-8 or NAP-2 as well as in their unloaded state revealed the occurrence of a single CXCR-2 variant with an apparent size of 56 kDa.
10878382 1 Although CXCR-2 has been successfully cloned and expressed in several cell lines, the molecular properties of the native neutrophil-expressed receptor have remained largely undefined.
10878382 6 These receptors did not participate in ligand-induced receptor trafficking, while surface-expressed CXCR-2 was internalized and re-expressed following stimulation with NAP-2.
10878382 7 By enzymatic removal of one 9-kDa carbohydrate moiety in surface-expressed CXCR-2 we can show that neither NAP-2-induced trafficking nor signaling of the receptor is dependent on its full glycosylation.
10878382 4 According to deglycosylation experiments surface-expressed CXCR-2 carries two N-linked 9-kDa carbohydrate moieties that are both of complex structure.
10878382 5 In addition, two other CXCR-2 variants of 38 and 40 kDa were found to occur exclusively intracellular and to carry N-glycosylations of high mannose or hybrid type.
10878382 8 Instead, glycosylation was found to protect CXCR-2 from proteolytic attack, as even partial deglycosylation is associated with serine protease-mediated disappearance of the receptor from the neutrophil surface.
20610741 2 Systemic injection of a small molecule CXCR2 antagonist at the onset of EAE decreased demyelinated lesions.
20610741 8 In vitro demyelinated CNS slice cultures also showed better myelin repair when CXCR2 was blocked with neutralizing antibodies or was genetically deleted.
12888558 10 Taken together, we conclude from these studies that CXCR2 functions as a dimer and that truncated receptors negatively modulate receptor activities competing for the formation of wt/wt dimers.
26497045 3 METHODS: Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center.
23650205 6 Cxcr2-CKO mice showed impaired neutrophil migration in sterile peritonitis.
23650205 7 Cxcr2-CKO mice reported here will provide a genetic reagent to dissect roles of CXCR2 in the neutrophil granulocyte lineage.
23650205 4 Without recombination Cxcr2(fl/fl) mice have CXCR2 expression on neutrophils in peripheral blood, bone marrow and spleen.
23650205 5 CXCR2-deficient neutrophils were observed in poly(I:C) treated Cxcr2(fl/fl) ::Mx-Cre(+) (Cxcr2-CKO) mice, but not in poly(I:C) treated Cxcr2(f//+) ::Mx-Cre(+) mice.
23650205 2 CXCR2 also promotes demyelination and decreases remyelination by actions toward hematopoietic cells and nonhematopoietic cells.
23650205 3 Germline CXCR2 deficient (Cxcr2(-/-) ) mice reported in 1994 revealed the complexity of CXCR2 function and its differential expression in varied cell-types.
23650205 1 Type 2 CXC chemokine receptor CXCR2 plays roles in development, tumorigenesis, and inflammation.
23650205 8 Furthermore Cxcr2(fl/fl) mice will provide useful genetic models to evaluate CXCR2 function in varied cell populations.
27826243 7 This is also associated with changes in pro-inflammatory chemokines and reduced incursion of γH2AX indicating CXCR2 deficient mice are protected from lung injury.
27826243 6 CXCR2 KO mice are protected from heightened inflammatory response mediated by increased neutrophil response as a result of acute 3 day CS exposure.
27826243 5 IL-6 levels in BALF were refractory to increase by CS in CXCR2 KO mice.
27826243 4 We used CXCR2-/- deficient/mutant (knock-out, KO) mice, and assessed the changes in critical lung inflammatory NF-κB-driven chemokines released from the parenchyma of CS-exposed mice.
27826243 3 We hypothesized that genetic ablation of CXCR2 would protect mice against CS-induced inflammation and DNA damage response.
27826243 2 The role CXCR2 in lung inflammation in response to cigarette smoke (CS) inhalation using the mutant mouse approach is not known.
27826243 1 Antagonism of CXCR2 receptors, predominately located on neutrophils and critical for their immunomodulatory activity, is an attractive pharmacological therapeutic approach aimed at reducing the potentially damaging effects of heightened neutrophil influx into the lung.
10747307 1 One such receptor, CXCR2, binds multiple CXC chemokines, including interleukin 8, GRO-alpha, GRO-beta, GRO-gamma, and NAP-2.
10747307 2 We have previously identified CXCR2 expression on myeloid cells, notably mature granulocytes, and projection neurons.
24582495 5 Proliferation assays, migration assays, and invasion assays were performed to confirm the suppressive effect of blocking CXCR2.
20540789 8 The CXCR2 (+ 1208) T allele manifested a significant association with an aggressive phenotype of breast carcinoma as defined by a large tumor size, a high histological grade, and auxiliary's lymph node metastasis.
20540789 9 Moreover, the presence of the IL-8 (-251) A and/or the CXCR2 (+ 1208) T allele showed a significant association with a decreased overall survival and disease-free survival in breast carcinoma patients.
20540789 4 Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis.
10747307 4 DESIGN: Archival specimens from normal neuroendocrine tissues and their malignant counterparts were analyzed by immunohistochemistry with monoclonal antibodies specific for CXCR1 and CXCR2.
20540789 6 RESULTS: A highly significant association was found between the homozygous CXCR2 (+ 1208) TT genotype (adjusted OR = 2.
20540789 7 The presence of two higher risk genotypes (the TA and TT in IL-8, and the TT in CXCR2) significantly increased the risk of developing breast carcinoma (adjusted OR = 4.
20540789 1 IL-8 acts through its CXCR1 and CXCR2 receptors.
20540789 2 CXCR2, expressed on the endothelial cells, is the receptor involved in mediating the angiogenic effects of ELR+CXC chemokines and in particular IL-8.
20540789 3 In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma.
24582495 1 CXC chemokine receptor 2 (CXCR2) has been associated with tumorigenesis and metastasis in human cancers.
27648130 4 Besides, immunohistochemical (IHC) staining was performed to investigate the expression of CXCR2/7 in adjacent normal tissues and tumor tissues from esophageal squamous cell carcinoma (ESCC) patients.
27648130 5 Also, the associations between CXCR2/7 expression and clinicopathological features and progression were explored.
27648130 6 The mRNA levels of CXCR2 and CXCR7 were significantly reduced after transfection.
27648130 7 Silencing of CXCR2 and CXCR7 statistically decreased cell viability and chemotaxis, and increased apoptotic rate.
31604030 4 CXCR2 Liver+/Myeloid+mice suffered higher liver injury than CXCR2Liver+/Myeloid-and CXCR2Liver-/Myeloid+, however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid-and CXCR2Liver-/Myeloid-) showed reduction of neutrophil accumulation around areas of necrosis.
27648130 1 Specific small interfering RNAs (siRNA) against CXCR2 and CXCR7 were transfected into EC cell lines TE-1, EC9706, and EC109 cells.
27648130 2 Expression of CXCR2 and CXCR7 was validated, along with cell viability, chemotaxis, apoptosis rate, and ERK1/2 pathways associated protein after transfection.
27648130 3 Moreover, EC9706 cells treated with or without CXCR2/7 siRNA were injected into athymic nude mice.
27648130 8 Cells invasion was significantly reduced by silencing of CXCR2, however, no significance was found in silencing of CXCR7.
27648130 9 The protein levels of pERK1/2 were significantly decreased by silencing of CXCR2 and CXCR7.
22274915 5 High expression of CXCR2 is also associated with short survival of LSCC patients.
22274915 4 The expression of CXCR2 in LSCC was significantly higher than that in tumor-adjacent tissues.
22274915 6 CXCR2 expression may serve as an independent prognostic marker for LSCC patients.
22274915 1 CXC-chemokine receptor type 2 (CXCR2) was reported to play critical roles in angiogenesis, tumorigenesis, and metastasis of several cancers such as colon cancer, melanoma, lung cancer, and so on.
22274915 3 Quantitative real-time reverse transcription-PCR and immunohistochemistry were used, respectively, to analyze the mRNA level and protein level of CXCR2 in 109 cases of LSCC tissues and 28 cases of tumor-adjacent normal tissues.
22274915 2 However, the expression of CXCR2 in LSCC and its association with clinical characters of LSCC remain unclear.
17405813 4 Expression of either of the RhoB mutants or transfection of RhoB siRNA impaired CXCR2-mediated chemotaxis.
17405813 5 Expression of RhoB T19N and transfection of RhoB siRNA impaired sorting of CXCR2 to the lysosome after 3 hours of CXCL8 stimulation and impaired CXCL8-induced CXCR2 degradation.
17405813 6 In cells expressing the RhoB Q63L mutant, CXCR2 recycling through the Rab11a recycling compartment was impaired after 30 minutes of CXCL8 stimulation as was CXCL8-induced CXCR2 degradation.
17405813 7 For cells expressing activated RhoB, CXCR2 colocalized with Rab4, a marker for the rapid recycling pathway, and with the mannose-6-phosphate receptor, which traffics between the trans-Golgi network and endosomes.
17405813 1 The CXCR2 chemokine receptor is a G-protein-coupled receptor that undergoes clathrin-mediated endocytosis upon ligand binding.
17405813 2 The trafficking of CXCR2 is crucial for cells to maintain a proper chemotactic response.
17405813 3 In this study, we used dominant-negative (T19N) and GTPase-deficient activated (Q63L) RhoB mutants, as well as RhoB small interfering RNA (siRNA) to investigate the role of RhoB in CXCR2 trafficking.
17405813 8 These data suggest that CXCR2 recycles through alternative pathways.
17405813 9 We conclude that oscillation of RhoB GTPase activity is essential for appropriate sorting decisions, and for directing CXCR2 degradation and recycling--events that are required for optimal chemotaxis.
12411301 8 In cells overexpressing Rab7-T22N, CXCR2 was retained in the Rab5- and Rab11a-positive endosomes after prolonged (4-hour) agonist treatment.
12411301 9 Our data suggest that the intracellular trafficking of CXCR2 is differentially regulated by Rab proteins.
23972657 10 These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.
12411301 3 However, overexpression of a dominant-negative Rab5-S34N mutant significantly attenuated CXCR2 sequestration.
12411301 1 The present study demonstrated that CXCR2 was colocalized with transferrin and low-density lipoprotein (LDL) after agonist treatment for different periods of time, suggesting 2 intracellular trafficking pathways for this receptor.
12411301 6 The colocalization of CXCR2 with LDL and LAMP-1 suggests that CXCR2 is targeted to lysosomes for degradation after prolonged ligand treatment.
12411301 7 However, the colocalization of CXCR2 with Lamp1 was blocked by the overexpression of a dominant-negative Rab7-T22N mutant.
12411301 4 The internalized CXCR2 was recycled back to the cell surface after removal of the agonist and recovery of the cells, but receptor recycling was inhibited by overexpression of a dominant-negative Rab11a-S25N mutant.
12411301 5 After prolonged (4-hour) agonist treatment, CXCR2 exhibited significantly increased colocalization with Rab7, which is localized in late endosomes.
28481874 1 In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis.
28481874 3 CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues.
28481874 2 Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples.
10653603 3 After 100 or 300 J/m(2) irradiation, a decrease in CXCR-2 mRNA was detectable from 12 h after irradiation; this downregulation was observed until 48 h after irradiation.
10653603 2 It has been shown that the expression of epidermal CXCR-2 is increased in psoriasis, suggesting that activation of KC mediated by CXCR-2 contributes to the characteristic epidermal changes observed in psoriasis.
10653603 1 IL-8 exerts its biological activities by binding to specific cell surface receptors, CXCR-1 and CXCR-2.
10653603 6 Our results indicate that UVB-induced growth inhibition of KC in hyperproliferative skin disorders may, in part, be related to downregulation of CXCR-2.
10653603 5 Immunohistochemical studies on two minimal erythema doses (2MED)-exposed and 2MED-unexposed skin from healthy volunteers revealed that CXCR-2 staining occurred over the whole layer of the epidermis but at 24 h after 2MED irradiation, the positive staining of CXCR-2 was decreased.
10653603 4 Immunohistochemical studies and flow cytometry analysis confirmed the suppressive effect of UVB on the expression of CXCR-2 protein in cultured human keratinocytes.
28481874 7 This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer.
28481874 6 Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression.

References
In this table a number of abstracts for CXCR2 are shown. The abstracts were obtained from the database based on the number of hits with CXCR2 or one of its synonyms. The search button in the top right can be used to only show abstracts with a particular additional keyword.

References
Functional defect of peripheral neutrophils in mice with induced deletion of CXCR2. Liping Liu;MeiZhang Li;Lisa C Spangler;Charles Spear;Mike Veenstra;Lindsey Darnall;Cathleen Chang;Anne C Cotleur;Richard M Ransohoff. 2013. Genesis. 51. PMID: 23650205

Type 2 CXC chemokine receptor CXCR2 plays roles in development, tumorigenesis, and inflammation. CXCR2 also promotes demyelination and decreases remyelination by actions toward hematopoietic cells and nonhematopoietic cells. Germline CXCR2 deficient (Cxcr2(-/-) ) mice reported in 1994 revealed the complexity of CXCR2 function and its differential expression in varied cell-types. Here, we describe Cxcr2(fl/fl) mice for which the targeting construct was generated by recombineering based on homologous recombination in E. coli. Without recombination Cxcr2(fl/fl) mice have CXCR2 expression on neutrophils in peripheral blood, bone marrow and spleen. Cxcr2(fl/fl) mice were crossed to Mx-Cre mice in which Cre recombinase is induced by Type I interferons, elicited by injection with polyinosinic-polycytidylic acid (poly(I:C)). CXCR2-deficient neutrophils were observed in poly(I:C) treated Cxcr2(fl/fl) ::Mx-Cre(+) (Cxcr2-CKO) mice, but not in poly(I:C) treated Cxcr2(f//+) ::Mx-Cre(+) mice. CXCR2 deletion was mainly observed peripherally but not in the CNS. Cxcr2-CKO mice showed impaired neutrophil migration in sterile peritonitis. Cxcr2-CKO mice reported here will provide a genetic reagent to dissect roles of CXCR2 in the neutrophil granulocyte lineage. Furthermore Cxcr2(fl/fl) mice will provide useful genetic models to evaluate CXCR2 function in varied cell populations.
Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction. Lei Wang;Xue-Chen Zhao;Wei Cui;Yong-Qiang Ma;Hua-Liang Ren;Xin Zhou;John Fassett;Yan-Zong Yang;Yingjie Chen;Yun-Long Xia;Jie Du;Hui-Hua Li. 2016. Circulation. 134. PMID: 27678262

BACKGROUND: The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown. METHODS: Angiotensin II (490 ng·kg-1·min-1) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry. RESULTS: Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45+ CXCR2+ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+ proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20). CONCLUSIONS: Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
Ligand-independent CXCR2 dimerization. Flavia Trettel;Sabrina Di Bartolomeo;Clotilde Lauro;Myriam Catalano;Maria Teresa Ciotti;Cristina Limatola. 2003. J Biol Chem. 278. PMID: 12888558

Homo- and hetero-oligomerization have been reported for several G protein-coupled receptors (GPCRs). The CXCR2 is a GPCR that is activated, among the others, by the chemokines CXCL8 (interleukin-8) and CXCL2 (growth-related gene product beta) to induce cell chemotaxis. We have investigated the oligomerization of CXCR2 receptors expressed in human embryonic kidney cells and generated a series of truncated mutants to determine whether they could negatively regulate the wild-type (wt) receptor functions. CXCR2 receptor oligomerization was also studied by coimmunoprecipitation of green fluorescent protein- and V5-tagged CXCR2. Truncated CXCR2 receptors retained their ability to form oligomers only if the region between the amino acids Ala-106 and Lys-163 was present. In contrast, all of the deletion mutants analyzed were able to form heterodimers with the wt CXCR2 receptor, albeit with different efficiency, competing for wt/wt dimer formation. The truncated CXCR2 mutants were not functional and, when coexpressed with wt CXCR2, interfered with receptor functions, impairing cell signaling and chemotaxis. When CXCR2 was expressed with the AMPA-type glutamate receptor GluR1, CXCR2 dimerization was again impaired in a dose-dependent way, and receptor functions were prejudiced. In contrast, CXCR1, a chemokine receptor that shares many similarities with CXCR2, did not dimerize alone or with CXCR2 and when coexpressed with CXCR2 did not impair receptor signaling and chemotaxis. The formation of CXCR2 dimers was also confirmed in cerebellar neuron cells. Taken together, we conclude from these studies that CXCR2 functions as a dimer and that truncated receptors negatively modulate receptor activities competing for the formation of wt/wt dimers.
Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion. Elisa A Liehn;Isabella Kanzler;Simone Konschalla;Andreas Kroh;Sakine Simsekyilmaz;Tolga Taha Sönmez;Richard Bucala;Jürgen Bernhagen;Christian Weber. 2013. Arterioscler Thromb Vasc Biol. 33. PMID: 23868943

OBJECTIVE: Here, we aimed to clarify the role of CXC chemokine receptor (CXCR) 2 in macrophage migration-inhibitory factor (MIF)-mediated effects after myocardial ischemia and reperfusion. As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2. In models of myocardial infarction, MIF exerts both proinflammatory effects and protective effects in cardiomyocytes. Similarly, CXCR2 displays opposing effects in resident versus circulating cells. APPROACH AND RESULTS: Using bone marrow transplantation, we generated chimeric mice with Cxcr2(-/-) bone marrow-derived inflammatory cells and wild-type (wt) resident cells (wt/Cxcr2(-/-)), Cxcr2(-/-) cardiomyocytes and wt bone marrow-derived cells (Cxcr2(-/-)/wt), and wt controls reconstituted with wt bone marrow (wt/wt). All groups were treated with anti-MIF or isotype control antibody before they underwent myocardial ischemia and reperfusion. Blocking MIF increased infarction size and impaired cardiac function in wt/wt and wt/CXCR2(-/-) mice but ameliorated functional parameters in Cxcr2(-/-)/wt mice, as analyzed by echocardiography and Langendorff perfusion. Neutrophil infiltration and angiogenesis were unaltered by MIF blockade or Cxcr2 deficiency. Monocyte infiltration was blunted in wt/Cxcr2(-/-) mice and reduced by MIF blockade in wt/wt and Cxcr2(-/-)/wt mice. Furthermore, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner. CONCLUSIONS: The compartmentalized and opposing effects of MIF after myocardial ischemia and reperfusion are largely mediated by CXCR2. Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CXCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function. These dichotomous findings should be considered when developing novel therapeutic strategies to treat myocardial infarction.
Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma. Masaharu Ogura;Hiroya Takeuchi;Hirofumi Kawakubo;Tomohiko Nishi;Kazumasa Fukuda;Rieko Nakamura;Tsunehiro Takahashi;Norihito Wada;Yoshiro Saikawa;Tai Omori;Taku Miyasho;Shingo Yamada;Yuko Kitagawa. 2013. Surgery. 154. PMID: 23972657

BACKGROUND: CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC. METHODS: The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed. RESULTS: Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P < .001), lymph node metastasis (pN factor; P = .001), pathologic stage (P < .001), lymphatic invasion (P = .010), and venous invasion (P = .001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P = .046, .009, .029, .010, and <.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P < .001) and disease-specific survival (P = .008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P = .008) was independent predictive factor for RFS. CONCLUSION: Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.
Cell-Specific Regulatory Effects of CXCR2 on Cholestatic Liver Injury. Takanori Konishi;Rebecca M Schuster;Holly S Goetzman;Charles C Caldwell;Alex B Lentsch. 2019. Am J Physiol Gastrointest Liver Physiol. . PMID: 31604030

CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability, but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2 -/- mice were subjected BDL. CXCR2 chimeric mice were created to assess cell specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibitor. CXCR2 -/- mice had significant less liver injury than wild-type mice at 3 days and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2 -/- mice showed significantly less neutrophil accumulation in those injured area. CXCR2 Liver+/Myeloid+and CXCR2Liver-/Myeloid-mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2 Liver+/Myeloid+mice suffered higher liver injury than CXCR2Liver+/Myeloid-and CXCR2Liver-/Myeloid+, however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid-and CXCR2Liver-/Myeloid-) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury.
Immunomodulatory role of CXCR2 during experimental septic peritonitis. Traci L Ness;Cory M Hogaboam;Robert M Strieter;Steven L Kunkel. 2003. J Immunol. 171. PMID: 14500678

The loss of CXCR2 expression by neutrophils is a well-described, but poorly understood, consequence of clinical sepsis. To address the potential impact of this CXCR2 deficit during the septic response, we examined the role of CXCR2 in a murine model of septic peritonitis provoked by cecal ligation and puncture (CLP). CLP-induced mouse mortality was significantly attenuated with i.v. or i.p. administration of an affinity-purified murine CXCR2-specific polyclonal Ab. Mouse survival required Ab administration before and every 2 days following CLP. Furthermore, mice deficient in CXCR2 (CXCR2(-/-)) were significantly protected against CLP-induced mortality compared with control (CXCR2(+/+)) mice. The anti-CXCR2 Ab treatment delayed, but did not completely inhibit, the recruitment of leukocytes, specifically neutrophils, into the peritoneal cavity. Peritoneal macrophages from anti-CXCR2 Ab-treated mice exhibited markedly increased RNA and protein levels of several key proinflammatory cytokines and chemokines. Specifically, isolated preparations of these cells released approximately 11-fold more CXCL10 protein compared with peritoneal macrophages from control-treated or naive mice. CXCR2(-/-) mice had higher resting and CLP-induced levels of peritoneal CXCL10 compared with CXCR2(+/+) mice. Administration of a neutralizing, affinity-purified, murine CXCL10-specific polyclonal Ab before CLP in wild-type mice and every 2 days after surgery significantly increased mortality compared with control Ab-treated mice. Anti-CXCL10 treatment in CXCR2(-/-) mice negated the protective effect associated with the absence of CXCR2. In summary, these data demonstrate that the absence of CXCR2 protects mice from septic injury potentially by delaying inflammatory cell recruitment and enhancing CXCL10 expression in the peritoneum.
Inducible cutaneous inflammation reveals a protumorigenic role for keratinocyte CXCR2 in skin carcinogenesis. Christophe Cataisson;Rebecca Ohman;Gopal Patel;Andrea Pearson;Margaret Tsien;Steve Jay;Lisa Wright;Henry Hennings;Stuart H Yuspa. 2009. Cancer Res. 69. PMID: 19118017

Transgenic mice that overexpress PKCalpha in the epidermis (K5-PKCalpha mice) exhibit acute CXCR2-mediated intraepidermal neutrophilic inflammation and a strong epidermal hyperplasia in response to application of 12-O-tetradecanoylphorbol-13-acetate (TPA). We now show that hyperplasia is independent of infiltrating neutrophils. Furthermore, when K5-PKCalpha mice were initiated with 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with a low dose of TPA, 58% of K5-PKCalpha mice developed skin papillomas that progressed to carcinoma, whereas wild-type mice did not develop tumors. We confirmed that CXCR2 is expressed by keratinocytes and showed that transformation by oncogenic ras (a hallmark of DMBA initiation) or TPA exposure induced all CXCR2 ligands. Ras induction of CXCR2 ligands was mediated by autocrine activation of epidermal growth factor receptor and nuclear factor-kappaB, and potentiated by PKCalpha. Oncogenic ras also induced CXCR2 ligands in keratinocytes genetically ablated for CXCR2. However, ras transformed CXCR2 null keratinocytes formed only small skin tumors in orthotopic skin grafts to CXCR2 intact hosts, whereas transformed wild-type keratinocytes produced large tumors. In vitro, CXCR2 was essential for CXCR2 ligand-stimulated migration of ras-transformed keratinocytes and for ligand activation of the extracellular signal-regulated kinase (ERK) and Akt pathways. Both migration and activation of ERK and Akt were restored by CXCR2 reconstitution of CXCR2 null keratinocytes. Thus, activation of CXCR2 on ras-transformed keratinocytes has both promigratory and protumorigenic functions. The up-regulation of CXCR2 ligands after initiation by oncogenic ras and promotion with TPA in the mouse skin model provides a mechanism to stimulate migration by both autocrine and paracrine pathways and contribute to tumor development.
Roles of hepatocyte and myeloid CXC chemokine receptor-2 in liver recovery and regeneration after ischemia/reperfusion in mice. Heather L Van Sweringen;Nozomu Sakai;Ralph C Quillin;Jeff Bailey;Rebecca Schuster;John Blanchard;Holly Goetzman;Charles C Caldwell;Michael J Edwards;Alex B Lentsch. 2012. Hepatology. 57. PMID: 22961770

UNLABELLED: Previous studies have demonstrated the significance of signaling through the CXC chemokine receptor-2 (CXCR2) receptor in the process of recovery and regeneration of functional liver mass after hepatic ischemia/reperfusion (I/R). CXCR2 is constitutively expressed on both neutrophils and hepatocytes; however, the cell-specific roles of this receptor are unknown. In the present study, chimeric mice were created through bone marrow transplantation (BMT) using wild-type and CXCR2-knockout mice, yielding selective expression of CXCR2 on hepatocytes (Hep) and/or myeloid cells (My) in the following combinations: Hep+/My+; Hep-/My+; Hep+/My-; and Hep-/My-. These tools allowed us to assess the contributions of myeloid and hepatocyte CXCR2 in the recovery of the liver after I/R injury. Flow cytometry confirmed the adoption of the donor phenotype in neutrophils. Interestingly, Kupffer cells from all chimeras lacked CXCR2 expression. Recovery/regeneration of hepatic parenchyma was assessed by histologic assessment and measurement of hepatocyte proliferation. CXCR2(Hep+/My+) mice showed the least amount of liver recovery and hepatocyte proliferation, whereas CXCR2(Hep-/My-) mice had the greatest liver recovery and hepatocyte proliferation. CXCR2(Hep+/My-) mice had enhanced liver recovery, with hepatocyte proliferation similar to CXCR2(Hep-/My-) mice. Myeloid expression of CXCR2 directly regulated CXC chemokine expression levels after hepatic I/R, such that mice lacking myeloid CXCR2 had markedly increased chemokine expression, compared with mice expressing CXCR2 on myeloid cells. CONCLUSION: The data suggest that CXCR2 on myeloid cells is the predominant regulator of liver recovery and regeneration after I/R injury, whereas hepatocyte CXCR2 plays a minor, secondary role. These findings suggest that myeloid cell-directed therapy may significantly affect liver regeneration after liver resection or transplantation.
CXCR2-driven ovarian cancer progression involves upregulation of proinflammatory chemokines by potentiating NF-κB activation via EGFR-transactivated Akt signaling. Yuan-Lin Dong;Syeda M Kabir;Eun-Sook Lee;Deok-Soo Son. 2014. PLoS One. 8. PMID: 24376747

Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines. Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector. Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells. TNF increased nuclear factor-κB (NF-κB) activity to a greater degree in CXCR2 transfected cells than control cells as well as provided a greater activation of IκB. CXCR2 transfected cells expressed higher levels of its proinflammatory ligands, CXCL1/2 and enhanced more proliferation, migration, invasion and colony formation. CXCR2 positive cells also activated more EGFR, which led to higher Akt activation. Enhanced NF-κB activity in CXCR2 positive cells was reduced by a PI3K/Akt inhibitor rather than an Erk inhibitor. CXCL1 added to CXCR2 positive cells led to an increased activation of IκB. CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-κB inhibitor, Bay 11-7082. In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF-κB inhibitor. Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-κB site. Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-κB activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.
Blockage of CXCR2 suppresses tumor growth of intrahepatic cholangiocellular carcinoma. Hideaki Sueoka;Tadamichi Hirano;Yugo Uda;Yuji Iimuro;Junichi Yamanaka;Jiro Fujimoto. 2014. Surgery. 155. PMID: 24582495

BACKGROUND/AIMS: Complete operative resection is the only approach to cure for intrahepatic cholangiocellular carcinoma (ICC), but the disease's prognosis is notably poor. A novel therapeutic approach is urgently required. CXC chemokine receptor 2 (CXCR2) has been associated with tumorigenesis and metastasis in human cancers. In this study, we investigated the suppressive effect of ICC growth by blocking CXCR2. MATERIAL AND METHODS: The role of CXCR2 was estimated using the human ICC cell lines, RBE and SSP25. CXCR2 small interfering RNA (siRNA) and an antagonist (SB225002) were used to block CXCR2. Proliferation assays, migration assays, and invasion assays were performed to confirm the suppressive effect of blocking CXCR2. Subcutaneous SSP25 tumors were established in athymic nude mice, and the mice were given SB225002. The expression of CXCR2 in ICC was determined by immunohistochemical staining of 34 ICC specimens. We investigated the relationship between CXCR2 expression and prognosis in ICC. RESULTS: The prognosis of patients who had higher CXCR2 expression in ICC was significantly poor (P = .004). CXCR2 siRNA treatment significantly suppressed CXCR2 expression in both RBE and SSP25. Cell proliferation, migration, and invasion were significantly suppressed by both CXCR2 siRNA and SB225002 compared with the control group. SB225002 also suppressed the growth of transplanted subcutaneous tumors (P = .02) CONCLUSION: Our results demonstrated that blocking CXCR2 clearly suppressed the development of ICC. Blocking CXCR2 may be a promising therapeutic approach for ICC.
Differential cross-regulation of the human chemokine receptors CXCR1 and CXCR2. Evidence for time-dependent signal generation. R M Richardson;B C Pridgen;B Haribabu;H Ali;R Snyderman. 1998. J Biol Chem. 273. PMID: 9726994

Neutrophils and transfected RBL-2H3 cells were used to investigate the mechanism of cross-regulation of the human interleukin-8 (IL-8) receptors CXCR1 and CXCR2 by chemoattractants. In neutrophils, Ca2+ mobilization by the CXCR2-specific chemokine, growth-related oncogene alpha (Groalpha), was desensitized by prior exposure to the chemoattractants N-formylated peptides (fMLP) or a complement cleavage product (C5a). In contrast, growth-related oncogene alpha did not desensitize the latter receptors. To investigate this phenomenon, CXCR2 was stably expressed in RBL-2H3 cells and mediated phosphoinositide hydrolysis, Ca2+ mobilization, chemotaxis, and secretion. In cells co-expressing CXCR2 and receptors for either C5a (C5aR) or fMLP (FR), CXCR2 was cross-phosphorylated and cross-desensitized by C5a and fMLP. However, neither C5aR nor FR was cross-phosphorylated or cross-desensitized by CXCR2 activation, although CXCR1 did mediate this process. Receptor internalization induced by IL-8 was more rapid and occurred at lower doses with CXCR2 than CXCR1, although both receptors mediated equipotent chemotaxis and exocytosis in RBL. Truncation of the cytoplasmic tail of CXCR2 (331T) prolonged its signaling relative to CXCR2, increased its resistance to internalization, and induced phospholipase D activation. 331T was resistant to homologous phosphorylation and cross-phosphorylation but not cross-desensitization of its Ca2+ mobilization by fMLP or C5a, indicating an inhibitory site distal to receptor/G protein coupling. In contrast to CXCR2, stimulation of 331T cross-desensitized Ca2+ mobilization by both FR and C5aR. CXCR2 and the mutant 331T induced phospholipase C beta3 phosphorylation to an extent equivalent to that of CXCR1. Taken together, these results suggest that CXCR1 and CXCR2 bind IL-8 to produce a group of equipotent responses, but their ability to generate other signals, including receptor internalization, cross-desensitization, and phospholipase D activation, are very different. The latter phenomena apparently require prolonged receptor activation, which in the case of CXCR2 is precluded by rapid receptor phosphorylation and internalization. Thus, receptors coupling to identical G proteins may trigger different cellular responses dependent on the length of their signaling time, which can be regulated by receptor phosphorylation.
CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis. Gong Yang;Daniel G Rosen;Guangzhi Liu;Fan Yang;Xiaoqing Guo;Xue Xiao;Fengxia Xue;Imelda Mercado-Uribe;Jiaoti Huang;Sue-Hwa Lin;Gordon B Mills;Jinsong Liu. 2010. Clin Cancer Res. 16. PMID: 20505188

PURPOSE: Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer. EXPERIMENTAL DESIGN: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-kappaB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples. RESULTS: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-kappaB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis. CONCLUSIONS: Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-kappaB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis.
Expression of interleukin-8 receptor CXCR2 and suppressor of cytokine signaling-3 in astrocytic tumors. Penelope Korkolopoulou;Georgia Levidou;Elias A El-Habr;Christos Adamopoulos;Vassilis Samaras;Athanasios Zisakis;Nikolaos Kavantzas;Efstathios Boviatsis;Paraskevi Fragkou;Athanasios G Papavassiliou;Efstratios Patsouris;Christina Piperi. 2012. Mol Med. 18. PMID: 22231733

The aim was to expand recently published information regarding the significance of the interleukin (IL)-8/p-STAT-3 (signal transducer and activator of transcription) pathway in astrocytomas, focusing on the IL-8 receptor, chemokine (C-X-C motif) receptor 2 (CXCR2), and the STAT-3 inhibitor SOCS-3 (suppressors of cytokine signaling). A total of 91 paraffin-embedded human astrocytoma tissues (grades II-IV) were investigated for the association of SOCS-3 and CXCR2 expression with clinicopathologic and morphometric microvascular characteristics, vascular endothelial growth factor (VEGF), IL-8 and p-STAT-3 expression and patient survival. Peripheral IL-8 secretion levels were assessed by enzyme-linked immunosorbent spot (ELISPOT). SOCS-3, p-STAT-3 and CXCR2 protein levels were also quantified by Western immunoblotting in six cases, and the protein levels of SOCS-3 and CXCR2 were correlated with the immunohistochemical expression of the respective proteins. All CXCR2-positive cases by Western immunoblotting displayed increased peripheral IL-8 secretion levels. Treatment of primary glioblastoma cell cultures with exogenous IL-8 enhanced proliferation, and this effect was inhibited by treatment with a neutralizing anti-CXCR2 antibody. SOCS-3 and CXCR2 were expressed by neoplastic astrocytes in 92.4% and 48.78% of cases, respectively, with their levels increasing with histological grade and extent of necrosis. VEGF expression and microvessel density, CXCR2 and IL-8 levels were interrelated. SOCS-3 and p-STAT-3 were co-expressed in 85.7% of cases, although they were not interrelated. In univariate survival analysis, increased SOCS-3 expression and the presence of CXCR2 adversely affected survival, whereas in multivariate analysis, only CXCR2 remained significant. The prognostic significance of CXCR2 was validated in an independent set of 63 patients. Our data implicate IL-8/CXCR2 signaling pathway in the progression and regulation of angiogenesis in astrocytomas and provide a rationale for CXCR2 therapeutic exploitation in these tumors.
CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma. Pierre Saintigny;Erminia Massarelli;Steven Lin;Young-Ho Ahn;Yulong Chen;Sangeeta Goswami;Baruch Erez;Michael S O'Reilly;Diane Liu;J Jack Lee;Li Zhang;Yuan Ping;Carmen Behrens;Luisa M Solis Soto;John V Heymach;Edward S Kim;Roy S Herbst;Scott M Lippman;Ignacio I Wistuba;Waun Ki Hong;Jonathan M Kurie;Ja Seok Koo. 2012. Cancer Res. 73. PMID: 23204236

CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine KRAS/p53-mutant lung adenocarcinoma cell line with high metastatic potential and an orthotopic syngeneic mouse model and in vitro using a CXCR2 small-molecule antagonist (SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis, and RAS pathway activation. Expression of CXCL5 was regulated by promoter methylation. The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.
Silencing of CXCR2 and CXCR7 protects against esophageal cancer. Kai Wu;Lingling Cui;Yang Yang;Jia Zhao;Dengyan Zhu;Donglei Liu;Chunyang Zhang;Yu Qi;Xiangnan Li;Weihao Li;Song Zhao. 2016. Am J Transl Res. 8. PMID: 27648130

This study was aimed to investigate the functional roles of cytokine receptor (CXCR) CXCR2 and CXCR7 in esophageal cancer (EC). Specific small interfering RNAs (siRNA) against CXCR2 and CXCR7 were transfected into EC cell lines TE-1, EC9706, and EC109 cells. Expression of CXCR2 and CXCR7 was validated, along with cell viability, chemotaxis, apoptosis rate, and ERK1/2 pathways associated protein after transfection. Moreover, EC9706 cells treated with or without CXCR2/7 siRNA were injected into athymic nude mice. Tumor volumes were measured. Besides, immunohistochemical (IHC) staining was performed to investigate the expression of CXCR2/7 in adjacent normal tissues and tumor tissues from esophageal squamous cell carcinoma (ESCC) patients. Also, the associations between CXCR2/7 expression and clinicopathological features and progression were explored. The mRNA levels of CXCR2 and CXCR7 were significantly reduced after transfection. Silencing of CXCR2 and CXCR7 statistically decreased cell viability and chemotaxis, and increased apoptotic rate. Cells invasion was significantly reduced by silencing of CXCR2, however, no significance was found in silencing of CXCR7. The protein levels of pERK1/2 were significantly decreased by silencing of CXCR2 and CXCR7. Besides, silencing of CXCR2 and CXCR7 significantly reduced tumor growth in vivo, and associated with clinicopathological features and progression. Silencing of CXCR2 and CXCR7 protects against EC by inhibiting cell growth and chemotaxis, and inducing apoptosis though ERK1/2 pathways. Silencing of CXCR2 and CXCR7 has potentially therapeutic target for EC.
Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis. Brett S Marro;Dominic D Skinner;Yuting Cheng;Jonathan J Grist;Laura L Dickey;Emily Eckman;Colleen Stone;Liping Liu;Richard M Ransohoff;Thomas E Lane. 2019. J Virol. 93. PMID: 31243125

CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia. Using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system, we were able to assess how timed ablation of Cxcr2 in oligodendroglia affected disease following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Generation of Plp-Cre-ER(T)::Cxcr2flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen. Ablation of oligodendroglia Cxcr2 did not influence clinical severity in response to intracranial infection with JHMV. Infiltration of activated T cells or myeloid cells into the central nervous system (CNS) was not affected, nor was the ability to control viral infection. In addition, the severity of demyelination was similar between tamoxifen-treated mice and vehicle-treated controls. Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice. Collectively, our findings argue that CXCR2 signaling in oligodendroglia is dispensable with regard to contributing to neuroinflammation, but its deletion enhances remyelination in a preclinical model of the human demyelinating disease multiple sclerosis (MS).IMPORTANCE Signaling through the chemokine receptor CXCR2 in oligodendroglia is important for developmental myelination in rodents, while chemical inhibition or nonspecific genetic deletion of CXCR2 appears to augment myelin repair in animal models of the human demyelinating disease multiple sclerosis (MS). To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen. Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination. These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases.
Phosphorylation-independent association of CXCR2 with the protein phosphatase 2A core enzyme. G H Fan;W Yang;J Sai;A Richmond. 2001. J Biol Chem. 276. PMID: 11278485

Protein phosphatase 2A (PP2A) is postulated to be involved in the dephosphorylation of G protein-coupled receptors. In the present study, we demonstrate that the carboxyl terminus of CXCR2 physically interacts with the PP2A core enzyme, a dimer formed by PP2Ac and PR65, but not with the PP2Ac monomer, suggesting direct interaction of the receptor with PR65. The integrity of a sequence motif in the C terminus of CXCR2, KFRHGL, which is conserved in all CC and CXC chemokine receptors, is required for the receptor binding to the PP2A core enzyme. CXCR2 co-immunoprecipitates with the PP2A core enzyme in HEK293 cells and in human neutrophils. Overexpression of dominant negative dynamin 1 (dynamin 1 K44A) in CXCR2-expressing cells blocks the receptor association with the PP2A core enzyme, and an internalization-deficient mutant form of CXCR2 (I323A,L324A) also exhibits impaired association with the PP2A core enzyme, suggesting that the receptor internalization is required for the receptor binding to PP2A. A phosphorylation-deficient mutant of CXCR2 (331T), which has previously been shown to undergo internalization in HEK293 cells, binds to an almost equal amount of the PP2A core enzyme in comparison with the wild-type CXCR2, suggesting that the interaction of the receptor with PP2A is phosphorylation-independent. The dephosphorylation of CXCR2 is reversed by treatment of the cells with okadaic acid. Moreover, pretreatment of the cells with okadaic acid increases basal phosphorylation of CXCR2 and attenuates CXCR2-mediated calcium mobilization and chemotaxis. Taken together, these data indicate that PP2A is involved in the dephosphorylation of CXCR2. We postulate that this interaction results from direct binding of the regulatory subunit A (PR65) of PP2A to the carboxyl terminus of CXCR2 after receptor sequestration and internalization.
Enhanced expression and clinical significance of chemokine receptor CXCR2 in hepatocellular carcinoma. Zhen Liu;Lei Yang;Jin Xu;Xiaobo Zhang;Baosheng Wang. 2009. J Surg Res. 166. PMID: 20018298

BACKGROUND: An ELR+ CXC chemokine receptor, CXCR2, was recently reported to be involved in tumorigenesis and development. However, the role of CXCR2 in hepatocellular carcinoma (HCC) is poorly understood. In this study, we aimed to investigate the association between CXCR2 expression and the biocharacteristics of HCC, and determine whether the expression of CXCR2 was related to the tumorigenesis and progression. METHODS: Forty-two patients who underwent hepatic resection and were diagnosed as HCC by histologic examination were included. HCC and corresponding adjacent tissues (distance from the tumor border exceeding 2 cm) were obtained. Twenty-three samples of normal liver tissue were acquired surgically from the patients who had received an operation due to liver trauma. CXCR2 mRNA and protein expressions were examined using semiquantitative reverse transcription-PCR and Western blot. RESULTS: Expression levels of CXCR2 were significantly increased in HCC compared with adjacent and normal liver tissues (P < 0.05). The results showed that CXCR2 mRNA and protein expression levels were not related to age, gender, AFP levels, tumor capsule, or tumor size. Also, there was no relationship between CXCR2 mRNA expression and TNM staging. The expression levels of CXCR2 mRNA and protein were correlated with intrahepatic metastasis (P < 0.05), portal cancer embolus (P < 0.05), and low differentiation (P < 0.05). Furthermore, the protein level of CXCR2 was relevant to TNM staging. The protein level of CXCR2 in stage III-IV was remarkably higher than in stage I-II (P < 0.05). CONCLUSION: Our data revealed that CXCR2 was able to promote invasion and metastasis of HCC. It may be a useful marker for judging biocharacteristics and prognosis of HCC.
The chemokine receptor-CXCR2 plays a critical role in the invasion and metastases of oral squamous cell carcinoma in vitro and in vivo. Yong Qian;Yu Wang;Duan-Shu Li;Yong-Xue Zhu;Zhong-Wu Lu;Qing-Hai Ji;Gong Yang. 2014. J Oral Pathol Med. 43. PMID: 24953191

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world with about 50% survival rate over 5 years. OSCC has a highly invasive potency and frequently metastasizes to the cervical lymph nodes, which is the principle reason leading to poor prognosis. CXCR2, the receptor of CXC chemokines, has been reported to be involved in invasion and metastasis in multiple types of malignancy. However, the accurate role of CXCR2 in OSCC has been little noticed. METHODS: In this study, we determined the expression of CXCR2 in OSCC using immunohistochemical staining (IHC) and analyzed the association between the expression of CXCR2 and the biobehavior of OSCC. Then, we established stable OSCC cell lines with interference of CXCR2 and observed the effect of CXCR2 knockdown on cell proliferation, migration, invasion, and morphological changes in vitro and in vivo. RESULTS: CXCR2 was positively expressed in 55.3% of OSCC patients and was statistically associated with the high cervical lymph node metastasis in OSCC. CXCR2 silencing markedly inhibited migration and invasion of OSCC cells in vitro and in vivo. Moreover, CXCR2 silencing led to morphological changes and decreased lamellipodial structures in OSCC cells. However, CXCR2 silencing showed no effect on proliferation of OSCC cells in vitro and in vivo. CONCLUSIONS: CXCR2 plays a critical role in the invasion and metastases of OSCC. And it is probably by regulating actin cytoskeletal remodeling that CXCR2 takes part in the invasion and metastases of OSCC.
Autocrine control of MIP-2 secretion from metastatic breast cancer cells is mediated by CXCR2: a mechanism for possible resistance to CXCR2 antagonists. Nuray Erin;Esra Nizam;Gamze Tanrıöver;Sadi Köksoy. 2015. Breast Cancer Res Treat. 150. PMID: 25682075

CXCR2 interacts with a wide range of chemokines and CXCR2 antagonists may have therapeutic value for treatment-resistant metastatic carcinomas. We aimed to explore regulation of activity of CXCR2 and its ligand, MIP-2, in metastatic breast carcinoma. We used mouse breast carcinoma cells metastasize to brain (4TBM), liver (4TLM), and heart (4THM) and explored the extra- and intracellular mechanisms effecting MIP-2 secretion using CXCR2 antagonist and inhibitors of downstream signaling molecules. 4TBM, 4TLM, and 4THM cells include cancer stem cell features and metastasize extensively. We also determined kinetics of MIP-2 secretion in 4T1 and non-metastatic 67NR mouse breast carcinoma cells. We found that there is an autocrine-inhibition of MIP-2 secretion. Specifically, metastatic cells selectively express CXCR2 only, and not CXCR1 and attenuating CXCR2 activity with SB225002 increased MIP-2 secretion. This may be due to the inhibition of protein kinase C (PKC) activity since RO318220; a specific inhibitor of PKC also increased MIP-2 secretion. Attenuating CXCR2 activity with SB225002, otherwise suppressed proliferation of 4THM and 4TBM cells. Tumor explants and cancer-associated fibroblasts obtained from 4TLM, 4THM, and 4TBM primary tumors secreted high levels of MIP-2. Surprisingly, CXCR2 expression was low in 4TLM cells demonstrating that liver metastatic cells might be resistant to the anti-tumoral effects of CXCR2 antagonists. Our results demonstrated that resistance to anti-proliferative effects of CXCR2 may also arise from feedback increases in MIP-2 secretion. Activation of PI3 K pathway augments MIP-2 secretion, hence possible resistance to the antitumor effects of CXCR2 antagonists might be prevented with inhibitors of PI3 K.
Genetic Ablation of CXCR2 Protects against Cigarette Smoke-Induced Lung Inflammation and Injury. Chad A Lerner;Wei Lei;Isaac K Sundar;Irfan Rahman. 2016. Front Pharmacol. 7. PMID: 27826243

Antagonism of CXCR2 receptors, predominately located on neutrophils and critical for their immunomodulatory activity, is an attractive pharmacological therapeutic approach aimed at reducing the potentially damaging effects of heightened neutrophil influx into the lung. The role CXCR2 in lung inflammation in response to cigarette smoke (CS) inhalation using the mutant mouse approach is not known. We hypothesized that genetic ablation of CXCR2 would protect mice against CS-induced inflammation and DNA damage response. We used CXCR2-/- deficient/mutant (knock-out, KO) mice, and assessed the changes in critical lung inflammatory NF-κB-driven chemokines released from the parenchyma of CS-exposed mice. The extent of tissue damage was assessed by the number of DNA damaging γH2AX positive cells. CXCR2 KO mice exhibited protection from heightened levels of neutrophils measured in BALF taken from mice exposed to CS. IL-8 (KC mouse) levels in the BALF from CS-exposed CXCR2 KO were elevated compared to WT. IL-6 levels in BALF were refractory to increase by CS in CXCR2 KO mice. There were no significant changes to MIP-2, MCP-1, or IL-1β. Total levels of NF-κB were maintained at lower levels in CS-exposed CXCR2 KO mice compared to WT mice exposed to CS. Finally, CXCR2 KO mice were protected from lung cells positive for DNA damage response and senescence marker γH2AX. CXCR2 KO mice are protected from heightened inflammatory response mediated by increased neutrophil response as a result of acute 3 day CS exposure. This is also associated with changes in pro-inflammatory chemokines and reduced incursion of γH2AX indicating CXCR2 deficient mice are protected from lung injury. Thus, CXCR2 may be a pharmacological target in setting of inflammation and DNA damage in the pathogenesis of COPD.
A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis. Z Xiang;Z-J Zhou;G-K Xia;X-H Zhang;Z-W Wei;J-T Zhu;J Yu;W Chen;Y He;R E Schwarz;R A Brekken;N Awasthi;C-H Zhang. 2017. Oncogene. 36. PMID: 28481874

The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
Intracellular trafficking of human CXCR1 and CXCR2: regulation by receptor domains and actin-related kinases. Efrat Matityahu;Rotem Feniger-Barish;Tsipi Meshel;Alon Zaslaver;Adit Ben-Baruch. 2002. Eur J Immunol. 32. PMID: 12442335

In this study we investigated the regulation of CXCR1 and CXCR2 intracellular trafficking. First, we produced a chimeric CXCR2 receptor that contained the internalization motifs of both CXCR2 and CXCR1 (CXCR2: LLKIL sequence; CXCR1: C-terminal phosphorylation sites). Elevated levels of internalization were induced by different ELR-expressing CXC chemokines on the chimeric receptor, as compared to wild-type CXCR2. Analysis of inter-relationships between CXCR1 and CXCR2 during internalization indicated that the exposure of cells that expressed both CXCR1 and CXCR2 to CXCL8 or CXCL6 resulted in decreased levels of CXCR1 internalization as compared to those in cells that expressed only CXCR1. To characterize the role of actin-related components in CXCR1 and CXCR2 trafficking, wortmannin, a potent inhibitor of phosphatidylinositol kinases, was used. The presence of wortmannin during receptor recycling inhibited CXCR1 and CXCR2 re-expression following CXCL8-induced internalization, and resulted in a marked disruption of the proper organization of actin filaments. The kinase-dependent recycling process required CXCR2 C-terminal phosphorylation sites. Our results suggest that actin-related kinases are required for the proper functionality of actin filaments, which are the instrumental factors needed for receptor recycling. In all, CXCR1 and CXCR2 internalization and recycling are tightly regulated by receptor domains and by actin-related kinases.
Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. Michael P Keane;John A Belperio;Ying Y Xue;Marie D Burdick;Robert M Strieter. 2004. J Immunol. 172. PMID: 14978086

The Glu-Leu-Arg(+) (ELR(+)) CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of nonsmall cell lung cancer-derived angiogenic activity and support tumorigenesis. ELR(+) CXC chemokines share a common chemokine receptor, CXCR2. We hypothesized that CXCR2 mediates the proangiogenic effects of ELR(+) CXC chemokines during tumorigenesis. To test this postulate, we used syngeneic murine Lewis lung cancer (LLC; 3LL, H-2(b)) heterotopic and orthotopic tumor model systems in C57BL/6 mice replete (CXCR2(+/+)) and deficient in CXCR2 (CXCR2(-/-)). We first demonstrated a correlation of the expression of endogenous ELR(+) CXC chemokines with tumor growth and metastatic potential of LLC tumors. Next, we found that LLC primary tumors were significantly reduced in growth in CXCR2(-/-) mice. Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2(-/-) mice. Morphometric analysis of the primary tumors in CXCR2(-/-) mice demonstrated increased necrosis and reduced vascular density. These findings were further confirmed in CXCR2(+/+) mice using specific neutralizing Abs to CXCR2. The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR(+) CXC chemokines in a preclinical model of lung cancer.
RhoB plays an essential role in CXCR2 sorting decisions. Nicole F Neel;Lynne A Lapierre;James R Goldenring;Ann Richmond. 2007. J Cell Sci. 120. PMID: 17405813

The CXCR2 chemokine receptor is a G-protein-coupled receptor that undergoes clathrin-mediated endocytosis upon ligand binding. The trafficking of CXCR2 is crucial for cells to maintain a proper chemotactic response. The mechanisms that regulate the recycling/degradation sorting decision are unknown. In this study, we used dominant-negative (T19N) and GTPase-deficient activated (Q63L) RhoB mutants, as well as RhoB small interfering RNA (siRNA) to investigate the role of RhoB in CXCR2 trafficking. Expression of either of the RhoB mutants or transfection of RhoB siRNA impaired CXCR2-mediated chemotaxis. Expression of RhoB T19N and transfection of RhoB siRNA impaired sorting of CXCR2 to the lysosome after 3 hours of CXCL8 stimulation and impaired CXCL8-induced CXCR2 degradation. In cells expressing the RhoB Q63L mutant, CXCR2 recycling through the Rab11a recycling compartment was impaired after 30 minutes of CXCL8 stimulation as was CXCL8-induced CXCR2 degradation. For cells expressing activated RhoB, CXCR2 colocalized with Rab4, a marker for the rapid recycling pathway, and with the mannose-6-phosphate receptor, which traffics between the trans-Golgi network and endosomes. These data suggest that CXCR2 recycles through alternative pathways. We conclude that oscillation of RhoB GTPase activity is essential for appropriate sorting decisions, and for directing CXCR2 degradation and recycling--events that are required for optimal chemotaxis.
Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. Kaouther Snoussi;Wijden Mahfoudh;Noureddine Bouaouina;Meriem Fekih;Hedi Khairi;Ahmed N Helal;Lotfi Chouchane. 2010. BMC Cancer. 10. PMID: 20540789

BACKGROUND: Interleukin-8 (IL-8/CXCL-8) is a prototype of the ELR+CXC chemokines that play an important role in the promotion and progression of many human cancers including breast cancer. We have recently showed the implication of polymorphism (-251) T/A of IL-8 gene in the susceptibility and prognosis of breast carcinoma. IL-8 acts through its CXCR1 and CXCR2 receptors. CXCR2, expressed on the endothelial cells, is the receptor involved in mediating the angiogenic effects of ELR+CXC chemokines and in particular IL-8.In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma. We also confirmed the implication of IL-8 (-251) T/A polymorphism in a larger cohort. Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis. METHODS: We used the allele-specific polymerase chain reaction to characterize the variation of IL-8 and CXCR2 for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for breast cancer. Associations of the genetic marker with the rates of breast carcinoma-specific overall survival and disease-free survival were assessed using univariate and multivariate analyses. RESULTS: A highly significant association was found between the homozygous CXCR2 (+ 1208) TT genotype (adjusted OR = 2.89; P = 0.008) and breast carcinoma. A significantly increased risk of breast carcinoma was associated with IL-8 (-251) A allele (adjusted OR = 1.86; P = 0.001). The presence of two higher risk genotypes (the TA and TT in IL-8, and the TT in CXCR2) significantly increased the risk of developing breast carcinoma (adjusted OR = 4.15; P = 0.0004).The CXCR2 (+ 1208) T allele manifested a significant association with an aggressive phenotype of breast carcinoma as defined by a large tumor size, a high histological grade, and auxiliary's lymph node metastasis. A significant association between the IL-8 (-251) A allele and the aggressive form of breast carcinoma was also found.Moreover, the presence of the IL-8 (-251) A and/or the CXCR2 (+ 1208) T allele showed a significant association with a decreased overall survival and disease-free survival in breast carcinoma patients. CONCLUSION: Our results indicated that the polymorphisms in IL-8 and CXCR2 genes are associated with increased breast cancer risk, as well as disease progress, supporting our hypothesis for IL-8 and ELR+CXC chemokine receptor (CXCR2) involvement in breast cancer pathogenesis.
Role of chemokine receptor CXCR2 expression in mammary tumor growth, angiogenesis and metastasis. Kalyan C Nannuru;Bhawna Sharma;Michelle L Varney;Rakesh K Singh. 2012. J Carcinog. 10. PMID: 22368515

BACKGROUND: Chemokines and their receptors have long been known to regulate metastasis in various cancers. Previous studies have shown that CXCR2 expression is upregulated in malignant breast cancer tissues but not in benign ductal epithelial samples. The functional role of CXCR2 in the metastatic phenotype of breast cancer still remains unclear. We hypothesize that the chemokine receptor, CXCR2, mediates tumor cell invasion and migration and promotes metastasis in breast cancer. The objective of this study is to investigate the potential role of CXCR2 in the metastatic phenotype of mouse mammary tumor cells. MATERIALS AND METHODS: We evaluated the functional role of CXCR2 in breast cancer by stably downregulating the expression of CXCR2 in metastatic mammary tumor cell lines Cl66 and 4T1, using short hairpin RNA (shRNA). The effects of CXCR2 downregulation on tumor growth, invasion and metastatic potential were analyzed in vitro and in vivo. RESULTS: We demonstrated knock down of CXCR2 in Cl66 and 4T1 cells (Cl66-shCXCR2 and 4T1-shCXCR2) cells by reverse transcriptase polymerase chain reaction (RT-PCR) at the transcriptional level and by immunohistochemistry at the protein level. We did not observe a significant difference in in vitro cell proliferation between vector control and CXCR2 knock-down Cl66 or 4T1 cells. Next, we examined the invasive potential of Cl66-shCXCR2 cells by in vitro Matrigel invasion assay. We observed a significantly lower number (52 ± 5) of Cl66-shCXCR2 cells invading through Matrigel compared to control cells (Cl66-control) (182 ± 3) (P < 0.05). We analyzed the in vivo metastatic potential of Cl66-shCXCR2 using a spontaneous metastasis model by orthotopically implanting cells into the mammary fat pad of female BALB/c mice. Animals were sacrificed 12 weeks post tumor implantation and tissue samples were analyzed for metastatic nodules. CXCR2 downregulation significantly inhibited tumor cell metastasis. All the mice (n = 10) implanted with control Cl66 cells spontaneously developed lung metastasis, whereas a significantly lower number of mice (40%) implanted with Cl66-shCXCR2 cells exhibited lung metastases. CONCLUSIONS: Together, these results suggest that CXCR2 may play a critical role in breast cancer invasion and metastasis.
Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. Thomas Jamieson;Mairi Clarke;Colin W Steele;Michael S Samuel;Jens Neumann;Andreas Jung;David Huels;Michael F Olson;Sudipto Das;Robert J B Nibbs;Owen J Sansom. 2012. J Clin Invest. 122. PMID: 22922255

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.
CXCR2 inhibition suppresses acute and chronic pancreatic inflammation. Colin W Steele;Saadia A Karim;Mona Foth;Loveena Rishi;Joshua D G Leach;Ross J Porter;Colin Nixon;T R Jeffry Evans;C Ross Carter;Robert J B Nibbs;Owen J Sansom;Jennifer P Morton. 2015. J Pathol. 237. PMID: 25950520

Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways. The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild-type and Cxcr2(-/-) mice. Strikingly, Cxcr2(-/-) mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells. The pancreata of Cxcr2(-/-) mice were also substantially protected from damage during chronic pancreatitis. Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non-neutrophils contributes to the development of chronic pancreatitis. Importantly, pharmacological inhibition of CXCR2 in wild-type mice replicated the protection seen in Cxcr2(-/-) mice in acute and chronic models of pancreatitis. Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2. Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage. CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis.
CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation. Fengjiao Wu;Yawei Zhao;Tian Jiao;Dongyan Shi;Xingxing Zhu;Mingshun Zhang;Meiqing Shi;Hong Zhou. 2015. J Neuroinflammation. 12. PMID: 25990934

BACKGROUND: Chemokines and chemokine receptors cooperate to promote immune cell recruitment to the central nervous system (CNS). In this study, we investigated the roles of CXCR2 and CXCL1 in leukocyte recruitment to the CNS using a murine model of neuroinflammation. METHODS: Wild-type (WT), CXCL1(-/-), and CXCR2(-/-) mice each received an intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). Esterase staining and intravital microscopy were performed to examine neutrophil recruitment to the brain. To assess endothelial activation in these mice, the expression of adhesion molecules was measured via quantitative real-time polymerase chain reaction (PCR) and Western blotting. To identify the cellular source of functional CXCR2, chimeric mice were generated by transferring bone marrow cells between the WT and CXCR2(-/-) mice. RESULTS: Expression levels of the chemokines CXCL1, CXCL2, and CXCL5 were significantly increased in the brain following the i.c.v. injection of LPS. CXCR2 or CXCL1 deficiency blocked neutrophil infiltration and leukocyte recruitment in the cerebral microvessels. In the CXCR2(-/-) and CXCL1(-/-) mice, the cerebral endothelial expression of adhesion molecules such as P-selectin and VCAM-1 was dramatically reduced. Furthermore, the bone marrow transfer experiments demonstrated that CXCR2 expression on CNS-residing cells is essential for cerebral endothelial activation and leukocyte recruitment. Compared with microglia, cultured astrocytes secreted a much higher level of CXCL1 in vitro. Astrocyte culture conditioned medium significantly increased the expression of VCAM-1 and ICAM-1 in cerebral endothelial cells in a CXCR2-dependent manner. Additionally, CXCR2 messenger RNA (mRNA) expression in cerebral endothelial cells but not in microglia or astrocytes was increased following tumor necrosis factor-α (TNF-α) stimulation. The intravenous injection of the CXCR2 antagonist SB225002 significantly inhibited endothelial activation and leukocyte recruitment to cerebral microvessels. CONCLUSIONS: CXCL1 secreted by astrocytes and endothelial CXCR2 play essential roles in cerebral endothelial activation and subsequent leukocyte recruitment during neuroinflammation.
CXCR2 is decreased in preeclamptic placentas and promotes human trophoblast invasion through the Akt signaling pathway. Dongcai Wu;Honghai Hong;Xuan Huang;Linhuan Huang;Zhiming He;Qun Fang;Yanmin Luo. 2016. Placenta. 43. PMID: 27324095

INTRODUCTION: CXCR2, the receptor of the CXC chemokines, plays a critical role in cell migration and invasion in many types of cancer. It is unclear what impact CXCR2 may have on Preeclampsia (PE), a pregnancy-specific disease, which is related to insufficient trophoblast invasion. The aim of this study was to investigate the expression pattern of CXCR2 in the placentas of healthy and PE pregnancies, and to investigate the molecular mechanism of CXCR2 involvement in the development of PE. METHODS: CXCR2 expression levels in newly delivered placentas from 38 pregnant women with PE and 21 healthy pregnant women were detected using quantitative real-time PCR, immunohistochemistry and Western blot assays. The effect of CXCR2 on trophoblast invasion and the underlying mechanisms were examined in two trophoblast cell lines (HTR-8/SVneo and TEV-1 cells). RESULTS: CXCR2 mRNA and protein expression levels were significantly decreased in preeclamptic placentas than normal control. The invasive abilities of the two trophoblast cell lines were significantly inhibited when CXCR2 was silenced, but that CXCR2 overexpression promoted trophoblast cells invasion. In addition, silencing CXCR2 reduced the expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP9) and phosphorylated Akt (p-Akt). Furthermore, an Akt inhibitor suppressed the expression of MMP-2 and MMP-9. DISCUSSION: Our results suggest that the decreased CXCR2 may contribute to the development of preeclampsia through impairing trophoblast invasion by down-regulating MMP-2 and MMP-9 via the Akt signaling pathway.
Downregulation of CXCR-2 but not CXCR-1 expression by human keratinocytes by UVB. S Kondo;A Yoneta;H Yazawa;A Kamada;K Jimbow. 2000. J Cell Physiol. 182. PMID: 10653603

Interleukin-8 (IL-8) belongs to the CXC chemokine family. IL-8 exerts its biological activities by binding to specific cell surface receptors, CXCR-1 and CXCR-2. Both receptors bind IL-8 with high affinity but they have different affinities for MGSA/Groalpha and NAP-2. It has been shown that the expression of epidermal CXCR-2 is increased in psoriasis, suggesting that activation of KC mediated by CXCR-2 contributes to the characteristic epidermal changes observed in psoriasis. In order to examine the mechanism(s) by which UVB therapy is effective for several dermatoses including psoriasis, we sought to examine if UVB would modulate the expression of CXCR-1 and CXCR-2 in human keratinocytes (KC). Constitutive expression of CXCR-1 and CXCR-2 mRNA was detected by RT-PCR in normal cultured human KC. After 100 or 300 J/m(2) irradiation, a decrease in CXCR-2 mRNA was detectable from 12 h after irradiation; this downregulation was observed until 48 h after irradiation. In contrast, the CXCR-1 mRNA level was unchanged. Immunohistochemical studies and flow cytometry analysis confirmed the suppressive effect of UVB on the expression of CXCR-2 protein in cultured human keratinocytes. Immunohistochemical studies on two minimal erythema doses (2MED)-exposed and 2MED-unexposed skin from healthy volunteers revealed that CXCR-2 staining occurred over the whole layer of the epidermis but at 24 h after 2MED irradiation, the positive staining of CXCR-2 was decreased. A faint CXCR-1 staining was observed in the lower part of the epidermis both in unexposed and exposed skins. Our results indicate that UVB-induced growth inhibition of KC in hyperproliferative skin disorders may, in part, be related to downregulation of CXCR-2.
Differential regulation of CXCR2 trafficking by Rab GTPases. Guo-Huang Fan;Lynne A Lapierre;James R Goldenring;Ann Richmond. 2002. Blood. 101. PMID: 12411301

Intracellular trafficking of chemokine receptors plays an important role in fine-tuning the functional responses of neutrophils and lymphocytes in the inflammatory process and HIV infection. Although many chemokine receptors internalize through clathrin-coated pits, regulation of the receptor trafficking is not fully understood. The present study demonstrated that CXCR2 was colocalized with transferrin and low-density lipoprotein (LDL) after agonist treatment for different periods of time, suggesting 2 intracellular trafficking pathways for this receptor. CXCR2 was colocalized with Rab5 and Rab11a, which are localized in early and recycling endosomes, respectively, in response to agonist stimulation for a short period of time, suggesting a recycling pathway for the receptor trafficking. However, overexpression of a dominant-negative Rab5-S34N mutant significantly attenuated CXCR2 sequestration. The internalized CXCR2 was recycled back to the cell surface after removal of the agonist and recovery of the cells, but receptor recycling was inhibited by overexpression of a dominant-negative Rab11a-S25N mutant. After prolonged (4-hour) agonist treatment, CXCR2 exhibited significantly increased colocalization with Rab7, which is localized in late endosomes. The colocalization of CXCR2 with LDL and LAMP-1 suggests that CXCR2 is targeted to lysosomes for degradation after prolonged ligand treatment. However, the colocalization of CXCR2 with Lamp1 was blocked by the overexpression of a dominant-negative Rab7-T22N mutant. In cells overexpressing Rab7-T22N, CXCR2 was retained in the Rab5- and Rab11a-positive endosomes after prolonged (4-hour) agonist treatment. Our data suggest that the intracellular trafficking of CXCR2 is differentially regulated by Rab proteins.
CXCR1 and CXCR2 activation and regulation. Role of aspartate 199 of the second extracellular loop of CXCR2 in CXCL8-mediated rapid receptor internalization. Mohd W Nasser;Sandeep K Raghuwanshi;Kimberly M Malloy;Pavani Gangavarapu;Joong-Youn Shim;Krishna Rajarathnam;Ricardo M Richardson. 2007. J Biol Chem. 282. PMID: 17204468

CXCL8 (interleukin-8) interacts with two receptors, CXCR1 and CXCR2, to activate leukocytes. Upon activation, CXCR2 internalizes very rapidly relative to CXCR1 ( approximately 90% versus approximately 10% after 5 min). The C termini of the receptors have been shown to be necessary for internalization but are not sufficient to explain the distinct kinetics of down-regulation. To determine the structural determinant(s) that modulate receptor internalization, various chimeric and point mutant receptors were generated by progressively exchanging specific domains or amino acids between CXCR1 and CXCR2. The receptors were stably expressed in rat basophilic leukemia 2H3 cells and characterized for receptor binding, intracellular Ca(2+) mobilization, phosphoinositide hydrolysis, phosphorylation, internalization, and MAPK activation. The data herein indicate that the second extracellular loop (2ECL) of the receptors is critical for the distinct rate of internalization. Replacing the 2ECL of CXCR2 with that of CXCR1 (B(2ECL)A) or Asp(199) with its CXCR1 valine counterpart (B(D199V)A) delayed CXCR2 internalization similarly to CXCR1. Replacing Asp(199) with Asn (B(D199N)) restored CXCR2 rapid internalization. Structure modeling of the 2ECL of the receptors also suggested that Asp(199) plays a critical role in stabilizing and modulating CXCR2 rapid internalization relative to CXCR1. B(D199N) internalized rapidly but migrated as a single phosphorylated form like CXCR1 ( approximately 75 kDa), whereas B(2ECL)A and B(D199V)A showed slow and fast migrating forms like CXCR2 ( approximately 45 and approximately 65 kDa, respectively) but internalized like CXCR1. These data further undermine the role of receptor oligomerization in CXCL8 receptor internalization. Like CXCR1, B(D199V)A also induced sustained ERK activation and cross-desensitized Ca(2+) mobilization to CCR5 relative to B(D199N) and CXCR2. Altogether, the data suggest that the 2ECL of the CXCL8 receptors is important in modulating their distinct rate of down-regulation and thereby signal length and post-internalization activities.
Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro. Zhen Li;Ying Wang;Suiwei Dong;Chunlei Ge;Yanbin Xiao;Ruilei Li;Xiang Ma;Yuanbo Xue;Qi Zhang;Juan Lv;Qinghua Tan;Zhitao Zhu;Xin Song;Jing Tan. 2014. Cytokine. 69. PMID: 25022956

BACKGROUND: CXCR1 and CXCR2, cell surface receptors of interleukin-8, regulate cell migration and alteration of their expression has been associated with poor prognosis of various cancers. The aim of this study was to detect their expression in gastric cancer to identify associations with another cell adhesion molecule, matrix metalloproteinase-9 (MMP9), and with clinicopathological data ex vivo, and then explore their potential role in gastric cancer cells in vitro. MATERIALS AND METHODS: A total of 172 cases of gastric cancer tissue specimens were collected for immunohistochemical analysis of CXCR1, CXCR2, and MMP9 expression. Expression of CXCR1 and CXCR2 proteins was knocked in or down using their cDNA and shRNA, respectively, in gastric cancer cell lines to assess the changed cell phenotypes and gene expression. RESULTS: CXCR1, CXCR2, and MMP9 were expressed in 61.0%, 77.9%, and 75.6% of gastric cancer tissues, respectively. Moreover, CXCR1 and CXCR2 expression was associated with tumor differentiations, advanced clinical stages, lymph node, and distant metastasis of gastric cancer. Similarly, MMP9 expression was associated with CXCR1 and CXCR2. Expression of these three proteins was interrelated. In vitro study showed that levels of CXCR1 and CXCR2 proteins were associated with the capacity of gastric cancer cell migration, while knockdown of their expression inhibited gastric cancer cell migration and invasion abilities in vitro. In contrast, overexpression of CXCR1 and CXCR2 proteins promoted tumor cell migration and invasion. At the gene levels, knockdown of CXCR1 or CXCR2 expression suppressed expression of Ets-1, SRC-1, and JNK proteins and phosphorylated c-Jun and Erk1/2. Conversely, upregulation of CXCR1 or CXCR2 promoted expression of Ets-1, SRC-1, JNK, and c-Jun proteins and phosphorylated JNK, c-Jun and Erk1/2. CONCLUSIONS: These findings suggest that CXCR1 and CXCR2 play an important role in gastric cancer progression. Further study will be performed to investigate whether target of their expression can be used as a novel strategy in clinical control of gastric cancer metastasis.
Correlation of C-X-C chemokine receptor 2 upregulation with poor prognosis and recurrence in human glioma. Liu Yang;Zenghui Liu;Ronghua Wu;Qi Yao;Zhikai Gu;Mei Liu. 2015. Onco Targets Ther. 8. PMID: 26586954

C-X-C chemokine receptor 2 (CXCR2), a member of the G-protein-coupled receptor family, is an interleukin-8 receptor and results in the activation of neutrophils. To date, CXCR2 has been identified with many cell events, including inflammation, neovascularization, metastasis, and cell carcinogenesis. This study aimed to investigate alterations in the expression of CXCR2 in patients with brain gliomas and relationships with pathological grades and clinicopathological characteristics. Brain tissue specimens from 60 patients with glioma and 15 patients undergoing surgery for epilepsy (controls) were detected using streptavidin-perosidase immunohistochemistry. Western blotting was used to evaluate CXCR2 protein levels with fresh tissues derived from glioma cases or controls. Correlations between CXCR2 expression and clinicopathological characteristics were analyzed using SPSS software. The results showed high-grade gliomas with high CXCR2 expression as compared with normal tissues. The expression of CXCR2 was significantly related to high grades and recurrence of tumor but not to age or sex. During an in vitro wound healing assay, U251 migration was reduced when the CXCR2-specific inhibitor SB225002 was applied. Our results suggested that the high expression of CXCR2 in gliomas was closely correlated to the degree of malignancy and recurrence and that CXCR2 inhibition decreased the migration of glioma cells. Therefore, CXCR2 may serve as a potential therapeutic target for the recurrence and migration of gliomas.
Chemokine antagonists that discriminate between interleukin-8 receptors. Selective blockers of CXCR2. S A Jones;B Dewald;I Clark-Lewis;M Baggiolini. 1997. J Biol Chem. 272. PMID: 9195914

Human neutrophils express two interleukin (IL)-8 receptors, CXC chemokine receptor (CXCR) 1 and CXCR2. IL-8 with changes to the NH2-terminal ELR motif can block IL-8-induced neutrophil functions (Moser, B., Dewald, B., Barella, L., Schumacher, C., Baggiolini, M., and Clark-Lewis, I. (1993) J. Biol. Chem. 268, 7125-7128). We have now examined the effect of NH2-terminally modified analogs of IL-8, GROalpha, and PF4 on CXCR1 and CXCR2 independently. Using stable Jurkat transfectants expressing either CXCR1 or CXCR2, it was shown that analogs derived from IL-8 bound both IL-8 receptors with similar affinity and could block IL-8-induced Ca2+ mobilization. By contrast, analogs of GROalpha and PF4, (R)GROalpha and (R)PF4, bound only CXCR2 with high affinity and blocked Ca2+ mobilization induced only via CXCR2. The differential effect on CXCR1 and CXCR2 was also demonstrated in studies with isolated neutrophils. Thus (R)GROalpha and (R)PF4 inhibited only the GROalpha but not the IL-8-stimulated elastase release, and these two analogs had no effect on IL-8-elicited superoxide generation, a response that is mediated by CXCR1 but not by CXCR2. These results show that CXCR2 selective receptor antagonists can be generated based upon the secondary binding determinants of GROalpha and PF4. They also highlight the primary importance of CXCR1 in chemokine-mediated release of granule enzymes and superoxide generation. The selective antagonists described may be used in future studies on IL-8 receptor signaling to define distinct steps leading to various functional responses induced in neutrophils via CXCR1 and CXCR2.
Hepatocyte signaling through CXC chemokine receptor-2 is detrimental to liver recovery after ischemia/reperfusion in mice. Satoshi Kuboki;Thomas Shin;Nadine Huber;Thorsten Eismann;Elizabeth Galloway;Rebecca Schuster;John Blanchard;Michael J Edwards;Alex B Lentsch. 2008. Hepatology. 48. PMID: 18688883

UNLABELLED: CXC chemokines and their receptor, CXC chemokine receptor-2 (CXCR2), are important components of the hepatic inflammatory response to ischemia/reperfusion (I/R). However, direct effects of CXC chemokines on hepatocytes during this response have not been studied. Wild-type and CXCR2(-/-) mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 96 hours of reperfusion. CXCR2(-/-) mice had significantly less liver injury at all reperfusion times compared with wild-type mice. Early neutrophil recruitment (12 hours) was diminished in CXCR2(-/-) mice, but within 24 hours it was the same as that of wild-type mice. Hepatocyte proliferation and regeneration was accelerated in CXCR2(-/-) mice compared with wild-type mice. These effects were associated with increased activation of nuclear factor kappaB and signal transducers and activators of transcription-3, despite there being no difference in the expression of proliferative factors such as tumor necrosis factor alpha, interleukin-6, and hepatocyte growth factor. To establish whether the accelerated proliferation and regeneration observed in CXCR2(-/-) mice was due to effects on hepatocytes rather than just a generalized decrease in acute inflammatory injury, mice were treated with the CXCR2 antagonist, SB225002, after neutrophil recruitment and injury were maximal (24 hours after reperfusion). SB225002 treatment increased hepatocyte proliferation and regeneration in a manner identical to that observed in CXCR2(-/-) mice. Treatment of primary wild-type hepatocytes with macrophage inflammatory protein-2 revealed that low concentrations protected against cell death, whereas high concentrations induced cell death. These effects were absent in hepatocytes from CXCR2(-/-) mice. CONCLUSION: Our data suggest that hepatocyte CXCR2 regulates proliferation and regeneration after I/R injury and reveal important differences in the role of this receptor in liver regeneration and repair induced under different conditions that may be related to ligand concentration.
The collagen-breakdown product N-acetyl-Proline-Glycine-Proline (N-alpha-PGP) does not interact directly with human CXCR1 and CXCR2. Petra de Kruijf;Herman D Lim;Saskia A Overbeek;Guido J R Zaman;Aletta D Kraneveld;Gert Folkerts;Rob Leurs;Martine J Smit. 2010. Eur J Pharmacol. 643. PMID: 20599927

Neutrophils transmigrate from the blood into inflamed tissue via the interaction of chemokines produced in this tissue with chemokine receptors, such as CXCR1 and CXCR2, that are expressed on the membranes of neutrophils. Subsequently, activation of neutrophils will in turn lead to increased tissue damage and thereby enhanced clinical symptoms of inflammatory diseases like chronic obstructive pulmonary disease, inflammatory bowel disease and psoriasis. Besides chemokines, also the collagen-breakdown product N-acetyl-Proline-Glycine-Proline (N-alpha-PGP) attracts neutrophils. In a recent article (Weathington et al., 2006) it was suggested that N-alpha-PGP exerts its effect via CXCR1 and CXCR2. In this study, we show that N-alpha-PGP, in contrast to CXCL8, does not directly activate or interact with CXCR1 or CXCR2. N-alpha-PGP was not able to displace the radioligand [(125)I]CXCL8 from CXCR1 and CXCR2 expressing HEK293T cells or neutrophils. In addition, N-alpha-PGP did not displace the radioligand [(3)H]-SB265610, a CXCR2 antagonist, from CXCR2 expressing cells. Furthermore, N-alpha-PGP was not able to activate G protein signalling in cells expressing CXCR1 and CXCR2. N-alpha-PGP was also not able to recruit beta-arrestin2, an intracellular scaffolding protein involved in G protein-independent signalling, in cells expressing CXCR2. These studies indicate that N-alpha-PGP is not a ligand of CXCR1 or CXCR2.
High expression of CXCR2 is associated with tumorigenesis, progression, and prognosis of laryngeal squamous cell carcinoma. Liang Han;Bin Jiang;Hao Wu;Xudong Wang;Xiaojun Tang;Jianfei Huang;Jin Zhu. 2012. Med Oncol. 29. PMID: 22274915

The laryngeal squamous cell carcinoma (LSCC) is one of the most common cancers threatening people's life. CXC-chemokine receptor type 2 (CXCR2) was reported to play critical roles in angiogenesis, tumorigenesis, and metastasis of several cancers such as colon cancer, melanoma, lung cancer, and so on. However, the expression of CXCR2 in LSCC and its association with clinical characters of LSCC remain unclear. Quantitative real-time reverse transcription-PCR and immunohistochemistry were used, respectively, to analyze the mRNA level and protein level of CXCR2 in 109 cases of LSCC tissues and 28 cases of tumor-adjacent normal tissues. The expression of CXCR2 in LSCC was significantly higher than that in tumor-adjacent tissues. Moreover, the expression level of CXCR2 protein in LSCC was significantly related to lymph node metastasis (P=.022), histopathological grade (P=.038), and 5 years' survival (P=.007). Cox regression analysis revealed that CXCR2 expression (P=.031), as well as lymphatic metastasis (P=.026) and TNM classification (P=.042), is an independent prognostic marker of LSCC. High expression of CXCR2 is also associated with short survival of LSCC patients. Our data indicate that the expression of CXCR2 is associated with the development and progression of LSCC. CXCR2 expression may serve as an independent prognostic marker for LSCC patients.
Chemokine receptor CXCR2 is transactivated by p53 and induces p38-mediated cellular senescence in response to DNA damage. Haiyang Guo;Zhaojian Liu;Bing Xu;Huili Hu;Zhao Wei;Qiao Liu;Xiyu Zhang;Xuebin Ding;Yu Wang;Minnan Zhao;Yaoqin Gong;Changshun Shao. 2013. Aging Cell. 12. PMID: 23869868

Mammalian cells may undergo permanent growth arrest/senescence when they incur excessive DNA damage. As a key player during DNA damage response (DDR), p53 transactivates an array of target genes that are involved in various cellular processes including the induction of cellular senescence. Chemokine receptor CXCR2 was previously reported to mediate replicative and oncogene-induced senescence in a DDR and p53-dependent manner. Here, we report that CXCR2 is upregulated in various types of cells in response to genotoxic or oxidative stress. Unexpectedly, we found that the upregulation of CXCR2 depends on the function of p53. Like other p53 target genes such as p21, CXCR2 is transactivated by p53. We identified a p53-binding site in the CXCR2 promoter that responds to changes in p53 functional status. Thus, CXCR2 may act downstream of p53. While the senescence-associated secretory phenotype (SASP) exhibits a kinetics that is distinct from that of CXCR2 expression and does not require p53, it reinforces senescence. We further showed that the cellular senescence caused by CXCR2 upregulation is mediated by p38 activation. Our results thus demonstrate CXCR2 as a critical mediator of cellular senescence downstream of p53 in response to DNA damage.
A combination of in vitro techniques for efficient discovery of functional monoclonal antibodies against human CXC chemokine receptor-2 (CXCR2). Ronald S Boshuizen;Catherine Marsden;Johan Turkstra;Christine J Rossant;Jerry Slootstra;Clive Copley;Klaus Schwamborn. 2014. MAbs. 6. PMID: 25484047

BACKGROUND: Development of functional monoclonal antibodies against intractable GPCR targets. RESULTS: Identification of structured peptides mimicking the ligand binding site, their use in panning to enrich for a population of binders, and the subsequent challenge of this population with receptor overexpressing cells leads to functional monoclonal antibodies. CONCLUSION: The combination of techniques provides a successful strategic approach for the development of functional monoclonal antibodies against CXCR2 in a relatively small campaign. SIGNIFICANCE: The presented combination of techniques might be applicable for other, notoriously difficult, GPCR targets. SUMMARY: The CXC chemokine receptor-2 (CXCR2) is a member of the large 'family A' of G-protein-coupled-receptors and is overexpressed in various types of cancer cells. CXCR2 is activated by binding of a number of ligands, including interleukin 8 (IL-8) and growth-related protein α (Gro-α). Monoclonal antibodies capable of blocking the ligand-receptor interaction are therefore of therapeutic interest; however, the development of biological active antibodies against highly structured GPCR proteins is challenging. Here we present a combination of techniques that improve the discovery of functional monoclonal antibodies against the native CXCR2 receptor. The IL-8 binding site of CXCR2 was identified by screening peptide libraries with the IL-8 ligand, and then reconstructed as soluble synthetic peptides. These peptides were used as antigens to probe an antibody fragment phage display library to obtain subpopulations binding to the IL-8 binding site of CXCR2. Further enrichment of the phage population was achieved by an additional selection round with CXCR2 overexpressing cells as a different antigen source. The scFvs from the CXCR2 specific phage clones were sequenced and converted into monoclonal antibodies. The obtained antibodies bound specifically to CXCR2 expressing cells and inhibited the IL-8 and Gro-α induced ß-arrestin recruitment with IC50 values of 0.3 and 0.2 nM, respectively, and were significantly more potent than the murine monoclonal antibodies (18 and 19 nM, respectively) obtained by the classical hybridoma technique, elicited with the same peptide antigen. According to epitope mapping studies, the antibody efficacy is largely defined by N-terminal epitopes comprising the IL-8 and Gro-α binding sites. The presented strategic combination of in vitro techniques, including the use of different antigen sources, is a powerful alternative for the development of functional monoclonal antibodies by the classical hybridoma technique, and might be applicable to other GPCR targets.
The prognostic value of CXC-chemokine receptor 2 (CXCR2) in gastric cancer patients. Zhenglin Wang;Hao Liu;Zhenbin Shen;Xuefei Wang;Heng Zhang;Jing Qin;Jiejie Xu;Yihong Sun;Xinyu Qin. 2015. BMC Cancer. 15. PMID: 26497045

BACKGROUND: CXC chemokine receptor 2 (CXCR2) has been reported to play an important role in the proliferation and invasion of gastric cancer cells. The present study aims to investigate the impact of CXCR2 expression on the overall survival (OS) of gastric cancer patients after radical resection. METHODS: Intratumoral CXCR2 expression was evaluated with immunohistochemistry on tissue microarrays containing tumor samples of 357 gastric cancer patients from a single center. CXCR2 expression levels were correlated to clinicopathological variables and OS. RESULTS: CXCR2 expression was mainly located in the cytoplasm of gastric carcinoma cells. High CXCR2 expression was associated with poor tumor differentiation (p = 0.021), increased tumor depth (p < 0.001), lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001) and short OS (p = 0.001). CXCR2 expression was an independent prognostic factor for OS (p = 0.001) in multivariate analysis, and could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with gastric cancer. CONCLUSION: Intratumoral CXCR2 expression is a novel independent predictor for survival in gastric cancer patients. CXCR2 might be a promising therapeutic target of postoperative adjuvant treatment.
The Chemokine Receptor CXCR2 Supports Nociceptive Sensitization after Traumatic Brain Injury. De-Yong Liang;Xiaoyou Shi;Peng Liu;Yuan Sun;Peyman Sahbaie;Wen-Wu Li;David C Yeomans;J David Clark. 2017. Mol Pain. 13. PMID: 28845733

Abstract: Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. Chemokine receptors play an important role in both pain and brain injury. In the current work, we pursued the hypothesis that the epigenetically regulated CXC chemokine receptor 2 (CXCR2) is a crucial modulator of nociceptive sensitization induced by TBI. For these studies, we used the rat lateral fluid percussion model of TBI. Histone actyltransferase activity was blocked using anacardic acid beginning immediately following injury, or delayed for seven days prior to administration. The selective CXCR2 antagonist SCH527123 administered systemically or intrathecally was used to probe the role of chemokine signaling on mechanical hindpaw sensitization after TBI. The expression of the CXCR2 receptor was accomplished using real-time PCR, immunohistochemistry, and Western blotting, while epigenetic regulation was assessed using chromatin immunoprecipitation assay. The spinal levels of several pain-related mediators including CXCL1, an endogenous ligand for CXCR2, as well as brain-derived neurotrophic factor and prodynorphin were measured by enzyme-linked immunosorbent assay. We observed that anacardic acid potently blocked and reversed mechanical hindpaw sensitization after TBI. The same drug was able to prevent the upregulation of CXCR2 after TBI, but did not affect the spinal expression of other pain mediators. On the other hand, both systemically and intrathecally administered SCH527123 reversed hindpaw allodynia after TBI. Most of the spinal CXCR2 appeared to be expressed by spinal cord neurons. Chromatin immunoprecipitation experiments demonstrated TBI-enhanced association of the CXCR2 promoter with acetylated-H3K9 histone protein that was also reversible using anacardic acid. Taken together, our findings suggested that TBI causes the upregulation of spinal CXCR2 through an epigenetic mechanism ultimately supporting nociceptive sensitization. The use of CXCR2 antagonists may, therefore, be useful in pain resulting from TBI.
Interleukin-8 promotes cell migration via CXCR1 and CXCR2 in liver cancer. Huijuan Bi;Yu Zhang;Shanshan Wang;Wenhao Fang;Wenjun He;Lina Yin;Ying Xue;Zhixiang Cheng;Minghui Yang;Jilu Shen. 2019. Oncol Lett. 18. PMID: 31516616

Liver cancer (LC), which is one of the most common types of cancer worldwide, is notorious for its high morbidity and mortality rates. Interleukin-8 (IL-8), an important member of the CXC chemokine family that was originally classified as a potent neutrophil chemoattractant, has been shown to serve an important role in inflammation, tumor growth, invasion and metastasis through interactions with its receptors. However, the expression and functional roles of IL-8 and its receptors, CXC chemokine receptor (CXCR) 1 and CXCR2 in the progression of liver cancer remain to be fully elucidated. In the present study, it was shown that the mRNA levels of IL-8, CXCR1 and CXCR2 were increased in peripheral blood mononuclear cells from patients with liver cancer compared with those from patients with cirrhosis or normal controls (P<0.05). Higher levels of CXCR1, CXCR2 and IL-8 were associated with advanced tumor stage and increased risk of lymph node or distant metastasis. Immunohistochemistry showed that the IL-8, CXCR1 and CXCR2 proteins were expressed in the cytoplasm of hepatoma cells at higher intensities than those of normal controls (P<0.05). The semi-quantitative analysis revealed that the relative mean density of hepatic IL-8, CXCR1 and CXCR2 staining in liver cancer was significantly increased compared with that in normal liver tissues (P<0.05). The analysis revealed that the mRNA expression of IL-8 was positively associated with that of CXCR1 (r=0.618; P<0.05) and CXCR2 (r=0.569; P<0.05). The mRNA levels of CXCR1 and CXCR2 gradually increased with elevated expression of IL-8 in liver cancer. Experiments were performed using human Huh-7 and HepG2 cell lines, incubating cells with IL-8 and conducting in vitro migration and invasion assays. The results showed that the wound healing activity and migration of Huh-7 and HepG2 cells were increased by IL-8. Pretreatment of the cells with anti-CXCR1 or anti-CXCR2 (5 µM) for 30 min markedly inhibited IL-8-directed cell migration. Taken together, these results indicated that IL-8 promotes liver cancer cell migration via CXCR1 and CXCR2 and that targeting the CXCR1/2 may be a potential strategy for liver cancer treatment.
Expression of the chemokine receptor CXCR2 in normal and neoplastic neuroendocrine cells. T Tecimer;J Dlott;A Chuntharapai;A W Martin;S C Peiper. 2000. Arch Pathol Lab Med. 124. PMID: 10747307

BACKGROUND: Chemokines effect their proinflammatory and growth regulatory roles through interaction with serpentine receptors. One such receptor, CXCR2, binds multiple CXC chemokines, including interleukin 8, GRO-alpha, GRO-beta, GRO-gamma, and NAP-2. We have previously identified CXCR2 expression on myeloid cells, notably mature granulocytes, and projection neurons. OBJECTIVE: To determine the expression of CXCR2 by cells of the neuroendocrine system. DESIGN: Archival specimens from normal neuroendocrine tissues and their malignant counterparts were analyzed by immunohistochemistry with monoclonal antibodies specific for CXCR1 and CXCR2. RESULTS: Immunohistochemical analysis revealed high-level expression of CXCR2 by cells in the pituitary, adrenal medulla, pancreatic islets, thyroid C cells, scattered Kulchitsky cells in the bronchi, and counterpart neuroendocrine cells in the stomach, small bowel, colon, and appendix. Neuroendocrine neoplasms that demonstrated high-level CXCR2 expression included (1) primary carcinoids localized to the stomach, small bowel, colon, appendix, fallopian tube, ovary, and lung; (2) atypical carcinoids of the lung; (3) metastatic carcinoids; (4) pituitary adenomas; (5) pheochromocytomas; and (6) medullary carcinomas of the thyroid. Small cell lung carcinomas, large cell neuroendocrine carcinomas of the lung, small cell carcinoma of the cervix, Merkel cell carcinomas, neuroblastomas, and malignant melanomas lacked evidence of CXCR2 expression. CONCLUSIONS: The expression of CXCR2 by normal neuroendocrine cells and neoplastic counterparts that have retained phenotypic features of this differentiation program suggests that chemokines may play an important role in functions that are characteristic of this cell type. In addition, this raises the possibility that chemokines may modulate secretion of biologically active products of these cells and their neoplastic counterparts.
Identification of distinct surface-expressed and intracellular CXC-chemokine receptor 2 glycoforms in neutrophils: N-glycosylation is essential for maintenance of receptor surface expression. A Ludwig;J E Ehlert;H D Flad;E Brandt. 2000. J Immunol. 165. PMID: 10878382

The G protein-coupled CXC-chemokine receptor CXCR-2 mediates activation of neutrophil effector functions in response to multiple ligands, including IL-8 and neutrophil-activating peptide 2 (NAP-2). Although CXCR-2 has been successfully cloned and expressed in several cell lines, the molecular properties of the native neutrophil-expressed receptor have remained largely undefined. Here we report on the identification and characterization of distinct CXCR-2 glycoforms and their subcellular distribution in neutrophils. Immunoprecipitation and Western blot analyses of surface-expressed receptors covalently linked to IL-8 or NAP-2 as well as in their unloaded state revealed the occurrence of a single CXCR-2 variant with an apparent size of 56 kDa. According to deglycosylation experiments surface-expressed CXCR-2 carries two N-linked 9-kDa carbohydrate moieties that are both of complex structure. In addition, two other CXCR-2 variants of 38 and 40 kDa were found to occur exclusively intracellular and to carry N-glycosylations of high mannose or hybrid type. These receptors did not participate in ligand-induced receptor trafficking, while surface-expressed CXCR-2 was internalized and re-expressed following stimulation with NAP-2. By enzymatic removal of one 9-kDa carbohydrate moiety in surface-expressed CXCR-2 we can show that neither NAP-2-induced trafficking nor signaling of the receptor is dependent on its full glycosylation. Instead, glycosylation was found to protect CXCR-2 from proteolytic attack, as even partial deglycosylation is associated with serine protease-mediated disappearance of the receptor from the neutrophil surface. Thus, although not directly involved in signaling, glycosylation appears to be required to maintain neutrophil responsiveness to CXC-chemokines during inflammation.
Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. Jan Heidemann;Hitoshi Ogawa;Michael B Dwinell;Parvaneh Rafiee;Christian Maaser;Henning R Gockel;Mary F Otterson;David M Ota;Norbert Lugering;Wolfram Domschke;David G Binion. 2002. J Biol Chem. 278. PMID: 12496258

Angiogenesis plays a critical role in metastasis and tumor growth. Human tumors, including colorectal adenocarcinoma, secrete angiogenic factors, inducing proliferation and chemotaxis of microvascular endothelial cells, eventually leading to tumor neovascularization. The chemokine interleukin 8 (IL-8; CXCL8) exerts potent angiogenic properties on endothelial cells through interaction with its cognate receptors CXCR1 and CXCR2. As CXCR1 and CXCR2 expression is differentially regulated in tissue-specific endothelial cells and effects of IL-8 on intestinal endothelial cells are not defined, we characterized the potential IL-8-induced angiogenic mechanisms in primary cultures of human intestinal microvascular endothelial cells (HIMEC) and IL-8 receptor expression in human intestinal microvessels. CXCR1 and CXCR2 expression on HIMEC were defined using reverse transcriptase-PCR, immunohistochemistry, flow cytometry, and Western blot analysis. IL-8-induced downstream signaling events were assessed using immunoblot analysis and immunofluorescence. The angiogenic effects of IL-8 on HIMEC were determined using proliferation and chemotaxis assays. HIMEC responded to IL-8 with rapid stress fiber assembly, chemotaxis, enhanced proliferation, and phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2). HIMEC express CXCR2, but not CXCR1. Neutralizing antibodies to CXCR2 diminished IL-8-induced chemotaxis and stress fiber assembly. Specific inhibitors of ERK 1/2 and phosphoinositide 3-kinase abrogated endothelial tube formation and IL-8-induced chemotaxis in HIMEC. IL-8 elicits angiogenic responses in microvascular endothelial cells isolated from human intestine by engaging CXCR2. We confirmed tissue expression of CXCR2 in human intestinal microvessels. Supported by the notion that malignant colonic epithelial cells overexpress IL-8, CXCR2 blockade may be a novel target for anti-angiogenic therapy in colorectal adenocarcinoma.
Myelin repair is accelerated by inactivating CXCR2 on nonhematopoietic cells. LiPing Liu;Lindsey Darnall;Taofang Hu;Karen Choi;Thomas E Lane;Richard M Ransohoff. 2010. J Neurosci. 30. PMID: 20610741

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS and remyelination in MS ultimately fails. Although strategies to promote myelin repair are eagerly sought, mechanisms underlying remyelination in vivo have been elusive. CXCR2 is expressed on neutrophils and oligodendrocyte lineage cells in the CNS. CXCR2-positive neutrophils facilitate inflammatory demyelination in demyelination models such as experimental autoimmune encephalomyelitis (EAE) and cuprizone intoxication. Systemic injection of a small molecule CXCR2 antagonist at the onset of EAE decreased demyelinated lesions. These results left the cellular target of the CXCR2 antagonist uncertain and did not clarify whether CXCR2 blockade prevented demyelination or promoted remyelination. Here, we show that the actions of CXCR2 on nonhematopoietic cells unexpectedly delay myelin repair. Bone marrow chimeric mice (Cxcr2(+/-)-->Cxcr2(-/-) and Cxcr2(+/-)-->Cxcr2(+/+)) were subjected to two distinct models of myelin injury. In all cases, myelin repair was more efficient in Cxcr2(+/-)-->Cxcr2(-/-) animals. Oligodendrocyte progenitor cells (OPCs) in demyelinated lesions of Cxcr2(+/-)-->Cxcr2(-/-) mice proliferated earlier and more vigorously than in tissues from Cxcr2(+/-)--> Cxcr2(+/+) animals. In vitro demyelinated CNS slice cultures also showed better myelin repair when CXCR2 was blocked with neutralizing antibodies or was genetically deleted. Our results suggest that CXCR2 inactivation permits optimal spatiotemporal positioning of OPCs in demyelinating lesions to receive local proliferative and differentiating signals. Given that CXCR2 exerts dual functions that promote demyelination and decrease remyelination by actions toward hematopoietic cells and nonhematopoietic cells, respectively, our findings identify CXCR2 as a promising drug target for clinical demyelinating disorders.