Interleukin 8 receptor, alpha explained

Interleukin 8 receptor, alpha is a chemokine receptor. This name and the corresponding gene symbol IL8RA have been replaced by the HGNC approved name C-X-C motif chemokine receptor 1 and the approved symbol CXCR1. It has also been designated as CD181 (cluster of differentiation 181). The IUPHAR Committee on Receptor Nomenclature and Drug Classification use the HGNC recommended name, CXCR1.

Function

The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein-activated second messenger system. Knockout studies in mice suggested that this protein inhibits embryonic oligodendrocyte precursor migration in developing spinal cord. IL8RA, IL8RB, which encodes another high affinity IL8 receptor, and IL8RBP, a pseudogene of IL8RB, form a gene cluster in a region mapped to chromosome 2q33-q36.^[1] Stimulation of CXCR1 in neutrophils by its primary ligand, Interleukin 8, leads to neutrophil chemotaxis and activation.^[2]

Clinical significance

Blocking CXCR1 (e.g., with repertaxin^[3]) inhibits some human breast cancer stem cells (in vitro and in mice).^[4]

In malignant melanoma expression of CXCR1 at the cell surface is present, independent of the cancers stage. It is thought to have a role in the cell growth and angiogenesis required for tumour survival. In this way it has been identified as a potential therapeutic target.^[5]

CXCR1 can be cleaved and inactivated by Neutrophil Derived Serine Proteases (NSPs), leading to neutrophil dysfunction and impaired bacterial killing in cystic fibrosis lung disease.^[6]

Interactions

Interleukin 8 receptor, alpha has been shown to interact with GNAI2.^{[7] [8]}

See also

• Interleukin
• Interleukin 8
• Interleukin 8 receptor, beta
• Interleukin receptor
• Interleukin-8 receptor

Further reading

• Ahuja SK, Ozçelik T, Milatovitch A, Francke U, Murphy PM . Molecular evolution of the human interleukin-8 receptor gene cluster . Nature Genetics . 2 . 1 . 31–36 . September 1992 . 1303245 . 10.1038/ng0992-31 . 19732372 .
• Lee J, Horuk R, Rice GC, Bennett GL, Camerato T, Wood WI . Characterization of two high affinity human interleukin-8 receptors . The Journal of Biological Chemistry . 267 . 23 . 16283–16287 . August 1992 . 1379593 . 10.1016/S0021-9258(18)41997-7 . free .
• Morris SW, Nelson N, Valentine MB, Shapiro DN, Look AT, Kozlosky CJ, Beckmann MP, Cerretti DP . Assignment of the genes encoding human interleukin-8 receptor types 1 and 2 and an interleukin-8 receptor pseudogene to chromosome 2q35 . Genomics . 14 . 3 . 685–691 . November 1992 . 1427896 . 10.1016/S0888-7543(05)80169-7 .
• Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI . Structure and functional expression of a human interleukin-8 receptor . Science . 253 . 5025 . 1278–1280 . September 1991 . 1840701 . 10.1126/science.1840701 . 1991Sci...253.1278H .
• Chuntharapai A, Lee J, Hébert CA, Kim KJ . Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes . Journal of Immunology . 153 . 12 . 5682–5688 . December 1994 . 7527448 . 10.4049/jimmunol.153.12.5682 . 8872590 . free .
• Chuntharapai A, Kim KJ . Regulation of the expression of IL-8 receptor A/B by IL-8: possible functions of each receptor . Journal of Immunology . 155 . 5 . 2587–2594 . September 1995 . 7650389 . 10.4049/jimmunol.155.5.2587 . 24746695 . free .
• Morohashi H, Miyawaki T, Nomura H, Kuno K, Murakami S, Matsushima K, Mukaida N . Expression of both types of human interleukin-8 receptors on mature neutrophils, monocytes, and natural killer cells . Journal of Leukocyte Biology . 57 . 1 . 180–187 . January 1995 . 7829970 . 10.1002/jlb.57.1.180 . 7819367 .
• Schönbeck U, Brandt E, Petersen F, Flad HD, Loppnow H . IL-8 specifically binds to endothelial but not to smooth muscle cells . Journal of Immunology . 154 . 5 . 2375–2383 . March 1995 . 7868904 . 10.4049/jimmunol.154.5.2375 . 31884586 . free .
• Ahuja SK, Shetty A, Tiffany HL, Murphy PM . Comparison of the genomic organization and promoter function for human interleukin-8 receptors A and B . The Journal of Biological Chemistry . 269 . 42 . 26381–26389 . October 1994 . 7929358 . 10.1016/S0021-9258(18)47205-5 . free .
• Sprenger H, Lloyd AR, Meyer RG, Johnston JA, Kelvin DJ . Genomic structure, characterization, and identification of the promoter of the human IL-8 receptor A gene . Journal of Immunology . 153 . 6 . 2524–2532 . September 1994 . 8077663 . 10.4049/jimmunol.153.6.2524 . 12014231 . free .
• Schnitzel W, Monschein U, Besemer J . 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 . Journal of Leukocyte Biology . 55 . 6 . 763–770 . June 1994 . 8195702 . 10.1002/jlb.55.6.763 . 5948202 .
• Wu D, LaRosa GJ, Simon MI . G protein-coupled signal transduction pathways for interleukin-8 . Science . 261 . 5117 . 101–103 . July 1993 . 8316840 . 10.1126/science.8316840 . 1993Sci...261..101W .
• Sebok K, Woodside D, al-Aoukaty A, Ho AD, Gluck S, Maghazachi AA . IL-8 induces the locomotion of human IL-2-activated natural killer cells. Involvement of a guanine nucleotide binding (Go) protein . Journal of Immunology . 150 . 4 . 1524–1534 . February 1993 . 8381837 . 10.4049/jimmunol.150.4.1524 . 29083621 . free .
• Cerretti DP, Kozlosky CJ, Vanden Bos T, Nelson N, Gearing DP, Beckmann MP . Molecular characterization of receptors for human interleukin-8, GRO/melanoma growth-stimulatory activity and neutrophil activating peptide-2 . Molecular Immunology . 30 . 4 . 359–367 . March 1993 . 8384312 . 10.1016/0161-5890(93)90065-J .
• Mollereau C, Muscatelli F, Mattei MG, Vassart G, Parmentier M . The high-affinity interleukin 8 receptor gene (IL8RA) maps to the 2q33-q36 region of the human genome: cloning of a pseudogene (IL8RBP) for the low-affinity receptor . Genomics . 16 . 1 . 248–251 . April 1993 . 8486366 . 10.1006/geno.1993.1167 .
• Lloyd A, Modi W, Sprenger H, Cevario S, Oppenheim J, Kelvin D . Assignment of genes for interleukin-8 receptors (IL8R) A and B to human chromosome band 2q35 . Cytogenetics and Cell Genetics . 63 . 4 . 238–240 . 1993 . 8500355 . 10.1159/000133541 .
• Damaj BB, McColl SR, Mahana W, Crouch MF, Naccache PH . Physical association of Gi2alpha with interleukin-8 receptors . The Journal of Biological Chemistry . 271 . 22 . 12783–12789 . May 1996 . 8662698 . 10.1074/jbc.271.22.12783 . free .
• Ahuja SK, Murphy PM . The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor . The Journal of Biological Chemistry . 271 . 34 . 20545–20550 . August 1996 . 8702798 . 10.1074/jbc.271.34.20545 . free .
• Damaj BB, McColl SR, Neote K, Songqing N, Ogborn KT, Hébert CA, Naccache PH . Identification of G-protein binding sites of the human interleukin-8 receptors by functional mapping of the intracellular loops . FASEB Journal . 10 . 12 . 1426–1434 . October 1996 . 8903513 . 10.1096/fasebj.10.12.8903513 . 9744575 . free .
• Jerva LF, Sullivan G, Lolis E . Functional and receptor binding characterization of recombinant murine macrophage inflammatory protein 2: sequence analysis and mutagenesis identify receptor binding epitopes . Protein Science . 6 . 8 . 1643–1652 . August 1997 . 9260277 . 2143775 . 10.1002/pro.5560060805 .

External links

• Web site: Chemokine Receptors: CXCR1 . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-03 . 2016-03-03 . https://web.archive.org/web/20160303192751/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2210 . dead .

Notes and References

1. Web site: Entrez Gene: IL8RA interleukin 8 receptor, alpha.
2. Bergin DA, Reeves EP, Meleady P, Henry M, McElvaney OJ, Carroll TP, Condron C, Chotirmall SH, Clynes M, O'Neill SJ, McElvaney NG . α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8 . The Journal of Clinical Investigation . 120 . 12 . 4236–4250 . December 2010 . 21060150 . 2993580 . 10.1172/JCI41196 .
3. Casilli F, Bianchini A, Gloaguen I, Biordi L, Alesse E, Festuccia C, Cavalieri B, Strippoli R, Cervellera MN, Di Bitondo R, Ferretti E, Mainiero F, Bizzarri C, Colotta F, Bertini R . Inhibition of interleukin-8 (CXCL8/IL-8) responses by repertaxin, a new inhibitor of the chemokine receptors CXCR1 and CXCR2 . Biochemical Pharmacology . 69 . 3 . 385–394 . February 2005 . 15652230 . 10.1016/j.bcp.2004.10.007 .
4. Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan JL, Dontu G, Wicha MS . CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts . The Journal of Clinical Investigation . 120 . 2 . 485–497 . February 2010 . 20051626 . 2810075 . 10.1172/JCI39397 .
   • Web site: January 5, 2010 . Investigators Find Method to Suppress Breast Cancer Stem Cells . Genetic Engineering & Biotechnology News . https://web.archive.org/web/20120806124335/http://www.genengnews.com/gen-news-highlights/investigators-find-method-to-suppress-breast-cancer-stem-cells/72269134/ . 2012-08-06.
5. Sharma B, Singh S, Varney ML, Singh RK . Targeting CXCR1/CXCR2 receptor antagonism in malignant melanoma . Expert Opinion on Therapeutic Targets . 14 . 4 . 435–442 . April 2010 . 20230195 . 4229031 . 10.1517/14728221003652471 .
6. Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, Krauss-Etschmann S, Koller B, Reinhardt D, Roscher AA, Roos D, Griese M . Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease . Nature Medicine . 13 . 12 . 1423–1430 . December 2007 . 18059279 . 10.1038/nm1690 . 9594986 .
7. Damaj BB, McColl SR, Neote K, Songqing N, Ogborn KT, Hébert CA, Naccache PH . Identification of G-protein binding sites of the human interleukin-8 receptors by functional mapping of the intracellular loops . FASEB Journal . 10 . 12 . 1426–1434 . October 1996 . 8903513 . 10.1096/fasebj.10.12.8903513 . 9744575 . free .
8. Damaj BB, McColl SR, Mahana W, Crouch MF, Naccache PH . Physical association of Gi2alpha with interleukin-8 receptors . The Journal of Biological Chemistry . 271 . 22 . 12783–12789 . May 1996 . 8662698 . 10.1074/jbc.271.22.12783 . free .