Alternative titles; symbols
HGNC Approved Gene Symbol: CXCL2
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:74,097,040-74,099,195 (from NCBI)
Chemokines are a group of small (approximately 8-14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines. CXC chemokines are further subdivided into ELR and non-ELR types based on the presence or absence of a glu-leu-arg sequence adjacent and N terminal to the CXC motif (summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
The GRO1 gene (CXCL1; 155730) was initially identified by Anisowicz et al. (1987) by its constitutive overexpression in spontaneously transformed Chinese hamster fibroblasts. (The name GRO stood for growth-related.) Subsequently, a protein with melanoma growth-stimulating activity (MGSA) was shown to be identical. Haskill et al. (1990) reported the identification of 2 other GRO genes, which they called GRO-beta and GRO-gamma (GRO3, CXCL3; 139111). These 2 share 90% and 86% identity at the deduced amino acid level with the original GRO-alpha isolate. One amino acid substitution, proline in GRO-alpha by leucine in GRO-beta and GRO-gamma, leads to a large predicted change in protein conformation. Significant differences were also found in the 3-prime untranslated region, including different numbers of ATTTA repeats associated with mRNA instability. DNA hybridization with oligonucleotide probes and partial sequence analysis of the genomic clones confirmed that the 3 forms are derived from related but different genes. Expression studies revealed tissue-specific regulation as well as regulation by specific inducing agents, including interleukin-1, tumor necrosis factor, and lipopolysaccharide.
Wolpe et al. (1989) showed that macrophages, in response to endotoxin, secrete a protein with a molecular mass of about 6,000 daltons and with an affinity for heparin. They termed this protein macrophage inflammatory protein-2 (MIP2). It is a potent chemotactic agent for polymorphonuclear leukocytes. Subcutaneous administration caused a localized inflammatory reaction. Partial N-terminal sequence data showed similarity to the family of proteins of which the archetype is platelet factor-4 (PF4; 173460). The sequence of the MIP2 gene was found to be most closely related to that of the GRO-beta gene.
Tekamp-Olson et al. (1990) used a cDNA clone of murine Mip2 to clone cDNAs for 2 human homologs, MIP2-alpha and MIP2-beta, which are highly homologous to each other and to the previously isolated gene for MGSA. Thus, the 3 GRO genes represent the human homologs of the murine Mip2 gene.
Haskill et al. (1990) reported the identification of 2 other GRO The GROB gene consists of 4 exons, 3 introns, and a 3-prime untranslated region of about 700 bp terminating at the polyadenylation site.
Studies by Haskill et al. (1990) indicated that the 3 GRO genes, GRO1, GRO2, AND GRO3, map to chromosome 4q21.
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999) localized a number of CXC chemokine genes to 4q12-q21. They proposed that the order in this region is centromere--IL8--GRO1/PPBP (121010)/PF4--SCYB5 (600324)/SCYB6 (138965)--GRO2/GRO3--SCYB11 (604852)--SCYB10 (147310)--MIG (601704)--telomere. The GRO2 gene was localized to 4q12-q13.
Nieuwenhuis et al. (2002) showed that clearance of intranasally applied Pseudomonas aeruginosa is impaired in the lungs of CD1d (188410)-deficient mice as well as in T cell-deficient mice. Failure to clear the bacteria was associated with a markedly reduced influx of neutrophils in the bronchoalveolar lavage fluid in the early stages of the infection, which was thought to result from impaired production of chemokines such as Mip2 by alveolar macrophages. Prior administration of alpha-galactosylceramide to wildtype mice induced almost complete eradication of P. aeruginosa from their lungs, indicating that activation of CD1d-restricted T cells by alpha-galactosylceramide is critical in host defense against these bacteria. Sequential radiologic, macroscopic pathology, and histopathologic analyses confirmed early enhanced inflammation and resolution of inflammation and bacterial phagocytosis by alveolar macrophages in the alpha-galactosylceramide-treated mice, whereas control mice exhibited higher numbers of bacteria, lung hemorrhage, and swelling. Flow cytometric analysis demonstrated that the macrophage activation in alpha-galactosylceramide-treated mice was associated with increased numbers of Ifng (147570)-producing NKT cells. Nieuwenhuis et al. (2002) concluded that activation of CD1d-restricted T cells is crucial in regulating the antimicrobial immune functions of macrophages at the lung mucosal surface and suggested that this activity may help in preventing colonization in diseases such as cystic fibrosis (219700) and in patients undergoing chemotherapy.
In diseased mouse and human arteries, Zhao et al. (2004) demonstrated that 5-lipoxygenase (5-LO; 152390)-positive macrophages localize to areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in Apoe (107741) -/- mice. 5-LO deficiency markedly attenuated the formation of these aneurysms and was associated with reduced matrix metalloproteinase-2 (MMP2; 120360) activity and diminished plasma macrophage inflammatory protein-1-alpha (CCL3; 182283), but only minimally affected the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulated expression of CCL3 in macrophages and CXCL2 in endothelial cells. Zhao et al. (2004) concluded that the 5-LO pathway is linked to hyperlipidemia-dependent inflammation of the arterial wall and to the pathogenesis of aortic aneurysms through a potential chemokine intermediary route.
Anisowicz, A., Bardwell, L., Sager, R. Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells. Proc. Nat. Acad. Sci. 84: 7188-7192, 1987. [PubMed: 2890161] [Full Text: https://doi.org/10.1073/pnas.84.20.7188]
Haskill, S., Peace, A., Morris, J., Sporn, S. A., Anisowicz, A., Lee, S. W., Smith, T., Martin, G., Ralph, P., Sager, R. Identification of three related human GRO genes encoding cytokine functions. Proc. Nat. Acad. Sci. 87: 7732-7736, 1990. [PubMed: 2217207] [Full Text: https://doi.org/10.1073/pnas.87.19.7732]
Nieuwenhuis, E. E. S., Matsumoto, T., Exley, M., Schleipman, R. A., Glickman, J., Bailey, D. T., Corazza, N., Colgan, S. P., Onderdonk, A. B., Blumberg, R. S. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nature Med. 8: 588-593, 2002. [PubMed: 12042809] [Full Text: https://doi.org/10.1038/nm0602-588]
O'Donovan, N., Galvin, M., Morgan, J. G. Physical mapping of the CXC chemokine locus on human chromosome 4. Cytogenet. Cell Genet. 84: 39-42, 1999. [PubMed: 10343098] [Full Text: https://doi.org/10.1159/000015209]
Strieter, R. M., Polverini, P. J., Arenberg, D. A., Kunkel, S. L. The role of CXC chemokines as regulators of angiogenesis. Shock 4: 155-160, 1995. [PubMed: 8574748] [Full Text: https://doi.org/10.1097/00024382-199509000-00001]
Tekamp-Olson, P., Gallegos, C., Bauer, D., McClain, J., Sherry, B., Fabre, M., van Deventer, S., Cerami, A. Cloning and characterization of cDNAs for murine macrophage inflammatory protein 2 and its human homologues. J. Exp. Med. 172: 911-919, 1990. [PubMed: 2201751] [Full Text: https://doi.org/10.1084/jem.172.3.911]
Wolpe, S. D., Sherry, B., Juers, D., Davatelis, G., Yurt, R. W., Cerami, A. Identification and characterization of macrophage inflammatory protein 2. Proc. Nat. Acad. Sci. 86: 612-616, 1989. [PubMed: 2643119] [Full Text: https://doi.org/10.1073/pnas.86.2.612]
Zhao, L., Moos, M. P. W., Grabner, R., Pedrono, F., Fan, J., Kaiser, B., John, N., Schmidt, S., Spanbroek, R., Lotzer, K., Huang, L., Cui, J., Rader, D. J., Evans, J. F., Habenicht, A. J. R., Funk, C. D. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nature Med. 10: 966-973, 2004. [PubMed: 15322539] [Full Text: https://doi.org/10.1038/nm1099]
Zlotnik, A., Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12: 121-127, 2000. [PubMed: 10714678] [Full Text: https://doi.org/10.1016/s1074-7613(00)80165-x]