Alternative titles; symbols
HGNC Approved Gene Symbol: CXCR1
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:218,162,841-218,166,962 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | {AIDS, slow progression to} | 609423 | 3 |
Interleukin-8 (IL8; 146930) is a proinflammatory cytokine involved in chemoattraction and activation of neutrophils. Holmes et al. (1991) isolated a cDNA encoding an IL8 receptor, IL8RA, from human neutrophils. The deduced amino acid sequence of IL8RA showed that it belongs to the superfamily of receptors that couple to guanine nucleotide-binding proteins (G proteins). The sequence is 29% identical to that of receptors for the other neutrophil chemoattractants, fMet-Leu-Phe and C5a.
Palter et al. (2001) characterized the IL8 system, which includes IL8, its receptors IL8RA and IL8RB (146928), and its degradative enzyme aminopeptidase N (151530), in the human fallopian tube by immunohistochemistry. IL8 was found in the human fallopian tube predominantly in the epithelial cells and was present in greater amounts in the distal compared with the proximal tube. IL8RA and IL8RB localized in the tube in similar patterns. Aminopeptidase N was found in tubal stromal tissue at the epithelial-stromal border and perivascularly. The authors concluded that the IL8 system may be an active component of tubal physiology and that aminopeptidase N may limit the systemic effects of epithelial IL8.
Weathington et al. (2006) reported that the collagen- or extracellular matrix (ECM)-derived PGP peptide shares sequence and structural homology with neutrophil chemokines, such as CXCL1 (155730) and CXCL2 (139110). In vivo studies in mice and in vitro studies using human cells showed that PGP was chemotactic for neutrophils. PGP chemotactic activity could be blocked by antibodies to CXCR1 and CXCR2 (IL8RB) in vivo and in vitro, and neutrophils failed to accumulate in Cxcr2 -/- mice after PGP challenge. Mass spectrometric analysis showed that mouse airways inflamed after exposure to lipopolysaccharide produced PGP peptides, resulting in neutrophil recruitment. Chronic exposure to PGP caused alveolar enlargement and right ventricular hypertrophy in mice. Weathington et al. (2006) found that individuals with chronic obstructive pulmonary disease (COPD; see 606963) had detectable PGP in bronchoalveolar lavage fluid. They concluded that PGP activity links ECM degradation with neutrophil recruitment in airway inflammation.
Hartl et al. (2007) showed that IL8 promoted killing of Pseudomonas aeruginosa through CXCR1, but not CXCR2. Bacterial killing and CXCR1 expression were significantly reduced in bronchoalveolar lavage (BAL) and induced sputum neutrophils in patients with cystic fibrosis (CF; 219700) and, to a lesser extent, in patients with chronic obstructive pulmonary disease (COPD; see 606963) and bronchiectasis, regardless of P. aeruginosa infection status. The loss of CXCR1 expression and bacterial killing was greater in older CF patients. Inhibition of serine proteases in BAL inhibited or prevented CXCR1 loss. CXCR1 cleavage released glycosylated CXCR1 fragments that stimulated IL8 production via TLR2 (603028). Inhalation of alpha-1-antitrypsin (PI; 107400) by CF patients decreased the abundance of free elastase, increased CXCR1 and CD35 (CR1; 120620) expression on airway neutrophils, improved bacterial killing, and reduced P. aeruginosa numbers in sputum. Hartl et al. (2007) concluded that CXCR1 cleavage and its functional consequences represent an important pathophysiologic mechanism in CF and other neutrophilic airway diseases.
Morris et al. (1992) mapped the IL8RA gene to chromosome 2q35. Mollereau et al. (1993) assigned the IL8RA gene to the same region by in situ hybridization. Lloyd et al. (1993) assigned both the IL8RA and the IL8RB genes to chromosome 2 by polymerase chain reaction amplification and by Southern analysis of a panel of human/rodent somatic cell hybrid DNAs. The IL8R genes were further localized by in situ hybridization to 2q35.
Vasilescu et al. (2007) identified a CXCR1 haplotype (CXCR1-Ha; 146929.0001) carrying 2 SNPs that resulted in nonsynonymous amino acid changes: 92T-G (rs16858811), which caused a met31-to-arg change (M31R) in the N-terminal extracellular domain, and 1003C-T (rs1658808), which caused an arg335-to-cys change (R335C) in the C-terminal intracellular domain. Flow cytometric, RT-PCR, and Western blot analysis showed that expression of CXCR1-Ha in different cell lines led to reduced expression of CD4 (186940) and CXCR4 (162643) compared with cell lines transfected with the alternative haplotype. Human immunodeficiency virus (HIV)-1 (see 609423) isolates preferentially using the CXCR4 receptor were less efficient in infecting cells expressing CXCR1-Ha than those expressing the alternative haplotype. Patients infected with HIV-1 who progressed rapidly to acquired immunodeficiency syndrome (AIDS) were significantly less likely to have CXCR1-Ha compared with patients who progressed slowly to AIDS. Vasilescu et al. (2007) concluded that the CXCR1-Ha allele protects against rapid progression to AIDS by modulating CD4 and CXCR4 expression.
Vasilescu et al. (2007) identified a CXCR1 haplotype (CXCR1-Ha) carrying 2 SNPs that resulted in nonsynonymous amino acid changes: 92T-G (rs16858811), which caused a met31-to-arg change (M31R) in the N-terminal extracellular domain, and 1003C-T (rs1658808), which caused an arg335-to-cys change (R335C) in the C-terminal intracellular domain. They found that the frequency of the CXCR1-Ha haplotype was significantly lower in 84 French HIV-1-infected patients who progressed rapidly to AIDS (see 609423) compared with 253 French HIV-1-infected patients who progressed slowly to AIDS. Vasilescu et al. (2007) concluded that the CXCR1-Ha allele protects against rapid progression to AIDS by modulating CD4 (186940) and CXCR4 (162643) expression.
Hartl, D., Latzin, P., Hordijk, P., Marcos, V., Rudolph, C., Woischnik, M., Krauss-Etschmann, S., Koller, B., Reinhardt, D., Roscher, A. A., Roos, D., Griese, M. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nature Med. 13: 1423-1430, 2007. [PubMed: 18059279] [Full Text: https://doi.org/10.1038/nm1690]
Holmes, W. E., Lee, J., Kuang, W.-J., Rice, G. C., Wood, W. I. Structure and functional expression of a human interleukin-8 receptor. Science 253: 1278-1280, 1991. [PubMed: 1840701] [Full Text: https://doi.org/10.1126/science.1840701]
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. Cytogenet. Cell Genet. 63: 238-240, 1993. [PubMed: 8500355] [Full Text: https://doi.org/10.1159/000133541]
Mollereau, C., Muscatelli, F., Mattei, M.-G., 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: 248-251, 1993. [PubMed: 8486366] [Full Text: https://doi.org/10.1006/geno.1993.1167]
Morris, S. W., Nelson, N., Valentine, M. B., Shapiro, D. N., Look, A. T., Kozlosky, C. J., Beckmann, M. P., Cerretti, D. P. Assignment of the genes encoding human interleukin-8 receptor types 1 and 2 and an interleukin-8 receptor pseudogene to chromosome 2q35. Genomics 14: 685-691, 1992. [PubMed: 1427896] [Full Text: https://doi.org/10.1016/s0888-7543(05)80169-7]
Palter, S. F., Mulayim, N., Senturk, L., Arici, A. Interleukin-8 in the human fallopian tube. J. Clin. Endocr. Metab. 86: 2660-2667, 2001. [PubMed: 11397869] [Full Text: https://doi.org/10.1210/jcem.86.6.7584]
Vasilescu, A., Terashima, Y., Enomoto, M., Heath, S., Poonpiriya, V., Gatanaga, H., Do, H., Diop, G., Hirtzig, T., Auewarakul, P., Lauhakirti, D., Sura, T., Charneau, P., Marullo, S., Therwath, A., Oka, S., Kanegasaki, S., Lathrop, M., Matsushima, K., Zagury, J.-F., Matsuda, F. A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients. Proc. Nat. Acad. Sci. 104: 3354-3359, 2007. [PubMed: 17360650] [Full Text: https://doi.org/10.1073/pnas.0611670104]
Weathington, N. M., van Houwelingen, A. H., Noerager, B. D., Jackson, P. L., Kraneveld, A. D., Galin, F. S., Folkerts, G., Nijkamp, F. P., Blalock, J. E. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nature Med. 12: 317-323, 2006. [PubMed: 16474398] [Full Text: https://doi.org/10.1038/nm1361]