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Gene Review

CXCR1  -  chemokine (C-X-C motif) receptor 1

Homo sapiens

Synonyms: C-C, C-C-CKR-1, C-X-C chemokine receptor type 1, CD128, CD181, ...
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Disease relevance of IL8RA


Psychiatry related information on IL8RA


High impact information on IL8RA

  • Major progress has been made in the understanding of chemokine actions on T lymphocytes that respond to several CC chemokines but also to IP10 and Mig, two CXC chemokines that selectively attract T cells via a novel receptor [7].
  • The immunoregulatory proteins C-C chemokines are potent chemoattractants of lymphocytes and monocytes, as well as activators and attractants of eosinophils and basophils [8].
  • We now report cloning of the genes for IL8RA, IL8RB and a recently inactivated pseudogene of receptor A (IL8RAP) [9].
  • We 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 [10].
  • Here we report the identification and characterization of a C-C chemokine (DC-CK1) that is specifically expressed by human dendritic cells at high levels [11].

Chemical compound and disease context of IL8RA


Biological context of IL8RA

  • IL8, IL8RA, and IL8RB SNPs were analyzed using a multiplex assay system, haplotypes were constructed, and risks were estimated using Cox proportional hazards models [16].
  • Several studies have shown that CC chemokines attract T lymphocytes, and that CD45RO+, memory phenotype cells are considered to be the main responders [17].
  • Blocking monoclonal antibodies (MoAbs) specific for CXCR-2 or CXCR-1 either suppress the first optimum of NAP-2-induced chemotaxis or drastically reduce the second one, respectively [18].
  • These observations suggest that down-regulation of CXCR expression may substantially reduce the responsiveness of phagocytosing neutrophils to CXC chemokines [19].
  • Compared with controls, a significant increase in the frequency of the CXCR-2 +785 CC homozygote and of the CXCR-2 +1208 TT homozygote was found in the SSc patients (37% versus 22% [P = 0.01] and 33% versus 17% [P = 0.003], respectively) [4].

Anatomical context of IL8RA

  • The prominent role of IL-2 in CC chemokine responsiveness of lymphocytes suggests that IL-2-mediated expansion is a prerequisite for the recruitment of antigen-activated T cells into sites of immune and inflammatory reactions [17].
  • In summary, this study clearly demonstrates that CXCR1 and CXCR2 are not expressed on human eosinophils, even after priming with different bioactive cytokines [20].
  • This potentiation correlated with enhanced binding to neutrophils and increased signaling through CXC chemokine receptor-1 (CXCR1), but it was significantly less pronounced on a CXCR2-expressing cell line [21].
  • Since systemic angiogenesis induced by IL-8 would more likely involve microvessel ECs, we investigated CXC receptor expression on human microvascular dermal endothelial cells (HMECs) [22].
  • Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes [23].

Associations of IL8RA with chemical compounds

  • Examination of the sequences of the CXC chemokines reveals that the highly conserved leucine, corresponding to Leu25 in IL-8, is always replaced by tyrosine in CC chemokines [24].
  • Ca(2+) mobilization by S3 and DeltaCCR1 were also cross-desensitized by CXCR1 and CXCR2 despite lack of receptor phosphorylation [25].
  • Activation of CXCR1 appears to depend significantly on the presence of a basic binding determinant close to the second cysteine [26].
  • Positive staining of transfectants, monocytes, and lymphocytes was inhibited by the GST protein fused with the NH2-terminal portion of CCR1, further indicating that this antibody recognized the NH2-terminal portion of CC CKR1 [27].
  • The LPS-induced reduction of neutrophil CXCR 1 and 2 expression, as determined by fluorescence-activated cell sorter analysis, was inhibited in volunteers receiving the high dose of the p38 MAPK inhibitor [28].

Physical interactions of IL8RA

  • This confirms the importance of this region in IL-8 in receptor binding and in conferring specificity between CXC and CC chemokines [29].
  • Only IL-8 and GCP-2 bind CXCR-1 with high affinity [30].
  • Human IL-8 receptor A binds with low affinity to MGSA or NAP-2 [31].
  • This cytokine belongs to the family of CXC chemokines, mediating the response through binding to the seven-transmembrane helical G protein-coupled receptors CXCR1 and CXCR2 [32].
  • MCP3 has been reported to interact with several C-C chemokine receptors, which can be simultaneously or selectively expressed on leukocyte subpopulations [33].

Regulatory relationships of IL8RA

  • Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes [17].
  • In addition, we demonstrate that podocytes release IL-8 in the presence of FCS and that IL-8 down-regulates cell surface CXCR1 [5].
  • The form in which IL-8 and NAP-2 bind to their specific receptors was analyzed in binding experiments with COS-1 cells expressing IL-8 receptor A or B in recombinant forms [34].
  • Sufficient stimulation of the CXCR1 terminated this cooperative relationship by downregulating surface expression of CXCR2 [35].
  • These findings suggest that a homolog or ortholog of hCXCR1 is expressed in the mouse to be activated by a hitherto unknown CXC chemokine of the mouse [36].

Other interactions of IL8RA

  • Crossdesensitization studies in PMNL enzyme release revealed crossreactivities with the NAP-1/IL-8-R on PMNL [37].
  • The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-alpha, despite their lack of CXCR2 expression [38].
  • METHODS: The presence of CC and CXC chemokine receptors on cultured FLS was studied at the messenger RNA (mRNA) level by reverse transcriptase-polymerase chain reaction and at the cell surface expression level by flow cytometry [39].
  • In contrast, the CC chemokines MCP-1 and eotaxin had little or no activity in the concentration range tested (up to 1 microg/ml) [40].
  • Expression of functional CCR and CXCR chemokine receptors in podocytes [5].

Analytical, diagnostic and therapeutic context of IL8RA


  1. IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation, and ploidy in myeloid metaplasia with myelofibrosis. Emadi, S., Clay, D., Desterke, C., Guerton, B., Maquarre, E., Charpentier, A., Jasmin, C., Le Bousse-Kerdilès, M.C. Blood (2005) [Pubmed]
  2. Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. Richardson, R.M., Tokunaga, K., Marjoram, R., Sata, T., Snyderman, R. J. Biol. Chem. (2003) [Pubmed]
  3. Up-regulation of macrophage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis. Homey, B., Dieu-Nosjean, M.C., Wiesenborn, A., Massacrier, C., Pin, J.J., Oldham, E., Catron, D., Buchanan, M.E., Müller, A., deWaal Malefyt, R., Deng, G., Orozco, R., Ruzicka, T., Lehmann, P., Lebecque, S., Caux, C., Zlotnik, A. J. Immunol. (2000) [Pubmed]
  4. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Renzoni, E., Lympany, P., Sestini, P., Pantelidis, P., Wells, A., Black, C., Welsh, K., Bunn, C., Knight, C., Foley, P., du Bois, R.M. Arthritis Rheum. (2000) [Pubmed]
  5. Expression of functional CCR and CXCR chemokine receptors in podocytes. Huber, T.B., Reinhardt, H.C., Exner, M., Burger, J.A., Kerjaschki, D., Saleem, M.A., Pavenstädt, H. J. Immunol. (2002) [Pubmed]
  6. Association between interleukin 1-beta promoter (-511) polymorphism and depressive symptoms in Alzheimer's disease. McCulley, M.C., Day, I.N., Holmes, C. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  7. Human chemokines: an update. Baggiolini, M., Dewald, B., Moser, B. Annu. Rev. Immunol. (1997) [Pubmed]
  8. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Neote, K., DiGregorio, D., Mak, J.Y., Horuk, R., Schall, T.J. Cell (1993) [Pubmed]
  9. Molecular evolution of the human interleukin-8 receptor gene cluster. Ahuja, S.K., Ozçelik, T., Milatovitch, A., Francke, U., Murphy, P.M. Nat. Genet. (1992) [Pubmed]
  10. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Kaneider, N.C., Agarwal, A., Leger, A.J., Kuliopulos, A. Nat. Med. (2005) [Pubmed]
  11. A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells. Adema, G.J., Hartgers, F., Verstraten, R., de Vries, E., Marland, G., Menon, S., Foster, J., Xu, Y., Nooyen, P., McClanahan, T., Bacon, K.B., Figdor, C.G. Nature (1997) [Pubmed]
  12. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Ichiyama, K., Yokoyama-Kumakura, S., Tanaka, Y., Tanaka, R., Hirose, K., Bannai, K., Edamatsu, T., Yanaka, M., Niitani, Y., Miyano-Kurosaki, N., Takaku, H., Koyanagi, Y., Yamamoto, N. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  13. HIV type 1 glycoprotein 120 inhibits human B cell chemotaxis to CXC chemokine ligand (CXCL) 12, CC chemokine ligand (CCL)20, and CCL21. Badr, G., Borhis, G., Treton, D., Moog, C., Garraud, O., Richard, Y. J. Immunol. (2005) [Pubmed]
  14. Protection against parenteral HIV-1 infection by homozygous deletion in the C-C chemokine receptor 5 gene. Kupfer, B., Kaiser, R., Brackmann, H.H., Effenberger, W., Rockstroh, J.K., Matz, B., Schneweis, K.E. AIDS (1999) [Pubmed]
  15. Expression of the chemokine receptors CXCR1 and CXCR2 on granulocytes in human endotoxemia and tuberculosis: involvement of the p38 mitogen-activated protein kinase pathway. Juffermans, N.P., Dekkers, P.E., Peppelenbosch, M.P., Speelman, P., van Deventer, S.J., van Der Poll, T. J. Infect. Dis. (2000) [Pubmed]
  16. Variants of the IL8 and IL8RB genes and risk for gastric cardia adenocarcinoma and esophageal squamous cell carcinoma. Savage, S.A., Abnet, C.C., Mark, S.D., Qiao, Y.L., Dong, Z.W., Dawsey, S.M., Taylor, P.R., Chanock, S.J. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  17. Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. Loetscher, P., Seitz, M., Baggiolini, M., Moser, B. J. Exp. Med. (1996) [Pubmed]
  18. The CXC-chemokine neutrophil-activating peptide-2 induces two distinct optima of neutrophil chemotaxis by differential interaction with interleukin-8 receptors CXCR-1 and CXCR-2. Ludwig, A., Petersen, F., Zahn, S., Götze, O., Schröder, J.M., Flad, H.D., Brandt, E. Blood (1997) [Pubmed]
  19. Phagocytosing neutrophils down-regulate the expression of chemokine receptors CXCR1 and CXCR2. Doroshenko, T., Chaly, Y., Savitskiy, V., Maslakova, O., Portyanko, A., Gorudko, I., Voitenok, N.N. Blood (2002) [Pubmed]
  20. The biologic role of interleukin-8: functional analysis and expression of CXCR1 and CXCR2 on human eosinophils. Petering, H., Götze, O., Kimmig, D., Smolarski, R., Kapp, A., Elsner, J. Blood (1999) [Pubmed]
  21. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Van den Steen, P.E., Proost, P., Wuyts, A., Van Damme, J., Opdenakker, G. Blood (2000) [Pubmed]
  22. Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells. Salcedo, R., Resau, J.H., Halverson, D., Hudson, E.A., Dambach, M., Powell, D., Wasserman, K., Oppenheim, J.J. FASEB J. (2000) [Pubmed]
  23. Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes. Chuntharapai, A., Lee, J., Hébert, C.A., Kim, K.J. J. Immunol. (1994) [Pubmed]
  24. Mutation of Leu25 and Val27 introduces CC chemokine activity into interleukin-8. Lusti-Narasimhan, M., Power, C.A., Allet, B., Alouani, S., Bacon, K.B., Mermod, J.J., Proudfoot, A.E., Wells, T.N. J. Biol. Chem. (1995) [Pubmed]
  25. Regulation of the human chemokine receptor CCR1. Cross-regulation by CXCR1 and CXCR2. Richardson, R.M., Pridgen, B.C., Haribabu, B., Snyderman, R. J. Biol. Chem. (2000) [Pubmed]
  26. Granulocyte chemotactic protein 2 acts via both IL-8 receptors, CXCR1 and CXCR2. Wolf, M., Delgado, M.B., Jones, S.A., Dewald, B., Clark-Lewis, I., Baggiolini, M. Eur. J. Immunol. (1998) [Pubmed]
  27. Preparation of specific polyclonal antibodies to a C-C chemokine receptor, CCR1, and determination of CCR1 expression on various types of leukocytes. Su, S.B., Mukaida, N., Wang, J., Nomura, H., Matsushima, K. J. Leukoc. Biol. (1996) [Pubmed]
  28. P38 mitogen activated protein kinase is involved in the downregulation of granulocyte CXC chemokine receptors 1 and 2 during human endotoxemia. van den Blink, B., Branger, J., Weijer, S., Gupta, A., van Deventer, S.J., Peppelenbosch, M.P., van der Poll, T. J. Clin. Immunol. (2004) [Pubmed]
  29. A molecular switch of chemokine receptor selectivity. Chemical modification of the interleukin-8 Leu25 --> Cys mutant. Lusti-Narasimhan, M., Chollet, A., Power, C.A., Allet, B., Proudfoot, A.E., Wells, T.N. J. Biol. Chem. (1996) [Pubmed]
  30. Chemokine regulation of neutrophil function in surgical inflammation. Williams, M.A., Cave, C.M., Quaid, G., Solomkin, J.S. Archives of surgery (Chicago, Ill. : 1960) (1999) [Pubmed]
  31. The N terminus of interleukin-8 (IL-8) receptor confers high affinity binding to human IL-8. Suzuki, H., Prado, G.N., Wilkinson, N., Navarro, J. J. Biol. Chem. (1994) [Pubmed]
  32. Semisynthesis and application of carboxyfluorescein-labelled biologically active human interleukin-8. David, R., Machova, Z., Beck-Sickinger, A.G. Biol. Chem. (2003) [Pubmed]
  33. Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptors. C-C CKR1, a receptor for macrophage inflammatory protein-1 alpha/Rantes, is also a functional receptor for MCP3. Ben-Baruch, A., Xu, L., Young, P.R., Bengali, K., Oppenheim, J.J., Wang, J.M. J. Biol. Chem. (1995) [Pubmed]
  34. Monomer-dimer equilibria of interleukin-8 and neutrophil-activating peptide 2. Evidence for IL-8 binding as a dimer and oligomer to IL-8 receptor B. Schnitzel, W., Monschein, U., Besemer, J. J. Leukoc. Biol. (1994) [Pubmed]
  35. CXCR2 stimulation primes CXCR1 [Ca2+]i responses to IL-8 in human neutrophils. Hauser, C.J., Fekete, Z., Goodman, E.R., Kleinstein, E., Livingston, D.H., Deitch, E.A. Shock (1999) [Pubmed]
  36. A homolog of the human chemokine receptor CXCR1 is expressed in the mouse. Moepps, B., Nuesseler, E., Braun, M., Gierschik, P. Mol. Immunol. (2006) [Pubmed]
  37. Lipopolysaccharide-stimulated human monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil-activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity. Schröder, J.M., Persoon, N.L., Christophers, E. J. Exp. Med. (1990) [Pubmed]
  38. Expression and regulation of chemokine receptors in human natural killer cells. Inngjerdingen, M., Damaj, B., Maghazachi, A.A. Blood (2001) [Pubmed]
  39. CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients. García-Vicuña, R., Gómez-Gaviro, M.V., Domínguez-Luis, M.J., Pec, M.K., González-Alvaro, I., Alvaro-Gracia, J.M., Díaz-González, F. Arthritis Rheum. (2004) [Pubmed]
  40. Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines. Sozzani, S., Luini, W., Borsatti, A., Polentarutti, N., Zhou, D., Piemonti, L., D'Amico, G., Power, C.A., Wells, T.N., Gobbi, M., Allavena, P., Mantovani, A. J. Immunol. (1997) [Pubmed]
  41. Expression and functional activity of the IL-8 receptor type CXCR1 and CXCR2 on human mast cells. Lippert, U., Artuc, M., Grützkau, A., Möller, A., Kenderessy-Szabo, A., Schadendorf, D., Norgauer, J., Hartmann, K., Schweitzer-Stenner, R., Zuberbier, T., Henz, B.M., Krüger-Krasagakes, S. J. Immunol. (1998) [Pubmed]
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