Alternative titles; symbols
HGNC Approved Gene Symbol: CXCL10
Cytogenetic location: 4q21.1 Genomic coordinates (GRCh38): 4:76,021,118-76,023,497 (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 (summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
Luster et al. (1985) showed that gamma-interferon (IFNG; 147570) regulates a gene that encodes a protein with amino acid homology to platelet factor-4 (PF4; 173460) and beta-thromboglobulin (see PPBP; 121010). Luster et al. (1987) reported the isolation of an interferon-inducible gene that encodes a 98-amino acid protein called IP10, which is secreted from a variety of cells, including monocytes, endothelial cells, and fibroblasts, in response to interferon. Homology to activating peptide IV (PFIV), beta-thromboglobulin (BTG), connective tissue-activating peptide III (CTAP-III), and other peptides associated with cell proliferation suggested that IP10 may be an important mediator of the inflammatory response to interferons.
A member of the alpha-chemokine family, IP10 inhibits bone marrow colony formation, has antitumor activity in vivo, is a chemoattractant for human monocytes and T cells, and promotes T cell adhesion to endothelial cells. Angiolillo et al. (1995) reported that IP10 is a potent inhibitor of angiogenesis in vivo. The authors noted that their results raised the possibility that IP10 may participate in the regulation of angiogenesis during inflammation and tumorigenesis.
Zhang et al. (1997) demonstrated that IP10 is a RAS (190020) target gene and is overexpressed in the majority of colorectal cancers.
Using nuclear magnetic resonance spectroscopy, Booth et al. (2002) showed that IP10 interacted with the N terminus of CXCR3 (300574) via a hydrophobic cleft formed by the N-loop and 40s-loop region of IP10, similar to the interaction surface of other chemokines, such as IL8 (146930). An additional region of interaction was found that consisted of a hydrophobic cleft formed by the N terminus and the 30s loop of IP10. Booth et al. (2002) suggested that a mechanism involving the 30s loop and the configuration of beta strand 2 may account for the interaction and antagonistic function of IP10 with CCR3 (601268).
Using semiquantitative RT-PCR analysis, Singh et al. (2003) detected increased expression of Ip10 and its receptor, Cxcr3, in mesenteric lymph nodes and inflamed colons of Il10 (124092) -/- mice. The Crohn disease (see 266600)-like colitis in Il10 -/- mice was associated with increased serum amyloid A (SAA; 104750), Il6 (147620), and Th1 cytokine levels and weight loss, all of which could be abrogated by anti-Ip10 treatment. Singh et al. (2003) concluded that anti-IP10 treatment can successfully impede development of inflammatory bowel disease, and that SAA levels can reveal the intensity of colitis.
Using microarray analysis, Feferman et al. (2005) found increased expression of Cxcl10 and its receptor, Cxcr3, in lymph node cells of rats with experimental autoimmune myasthenia gravis (MG; 254200). Real-time RT-PCR, FACS, and immunohistochemistry analyses confirmed these findings and revealed upregulated expression of another Cxcr3 chemoattractant, Cxcl9 (601704), and of Tnf (191160) and Il1b (147720), which act synergistically with Ifng to induce Cxcl10, in both lymph node cells and muscle of myasthenic rats. Upregulation of these genes was reduced after mucosal tolerance induction with an AChR (see CHRNA1; 100725) fragment. Using RT-PCR, flow cytometric, and fluorescence microscopy analyses, Feferman et al. (2005) found increased expression of CXCL10 and CXCR3 in thymus and muscle of MG patients compared with age-matched controls, validating their findings in the rat model of MG. They concluded that CXCL10/CXCR3 signaling is associated with MG pathogenesis and proposed that CXCL10 and CXCR3 may serve as novel drug targets to treat MG.
Harris et al. (2012) tracked T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in 2 different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell mobility in the brain is well described by a generalized Levy walk. According to the model of Harris et al. (2012), this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behavior is similar to Levy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets.
Luster et al. (1987) mapped the INP10 gene to 4q21 by in situ hybridization. This locus is associated with an acute monocytic/B-lymphocyte lineage leukemia that exhibits the nonrandom translocation t(4;11)(q21;q23). In situ hybridization of leukemic cells carrying this translocation showed that INP10 is proximal to the breakpoint. No DNA rearrangement was evident when the INP10 was hybridized to genomic DNA isolated from 2 patients with the translocation. The ETS1 oncogene (164720) is located at 11q23 and is known to be translocated to chromosome 4 in t(4;11)(q21;q23) and into the interferon gene cluster in leukemic cells carrying the translocation t(9;11)(p22;q23). Both translocations are associated with acute monocytic leukemia. These findings suggested to Luster et al. (1987) that the juxtaposition of genetic loci regulated by antiproliferative signals, such as interferon, next to an oncogene like ETS1, could effectively short circuit homeostatic control mechanisms and contribute to the neoplastic state. Wathelet et al. (1988) also mapped INP10 to chromosome 4.
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 (146930)--GRO1 (155730)/PPBP/PF4--SCYB5 (600324)/SCYB6 (138965)--GRO2 (139110)/GRO3 (139111)--SCYB11 (604852)--SCYB10--MIG (CXCL9)--telomere.
IP10 expression is upregulated by IFNs and inflammatory stimuli, and it is expressed in many Th1-type inflammatory diseases in a variety of tissues and cell types. By targeted gene disruption, Dufour et al. (2002) generated Ip10-deficient mice that were healthy and otherwise indistinguishable from wildtype mice. However, splenocytes from Ip10-deficient mice did not respond well to allogeneic cells or to exogenous antigen. Contact hypersensitivity responses were also diminished compared with wildtype mice. Mutant mice infected with a neurotropic strain of mouse hepatitis virus displayed an impaired ability to control viral replication in the brain, which was associated with decreased recruitment of Cd4-positive and Cd8-positive cells in the brain. RT-PCR and histologic analysis determined that Ifng, Mig (Cxcl9), and Scyb11 (Cxcl11) levels were also lower in the brains of Ip10 -/- mice and that there was reduced demyelination in the central nervous system. Dufour et al. (2002) concluded that IP10 plays a role in the generation and delivery of an effector T-cell response.
Rhode et al. (2005) generated transgenic mice expressing Cxcl10 under control of the rat insulin promoter (RIP) specifically in beta cells of the islets of Langerhans. These mice showed mononuclear cell infiltration and impairment of beta cell function, but they did not develop spontaneous diabetes. RIP-Cxcl10 mice crossed to RIP-nucleoprotein (NP) mice expressing lymphocytic choriomeningitis virus (LCMV) NP in beta cells had massively accelerated type I diabetes (222100) after LCMV infection. Fluorescent tetramer analysis demonstrated islet infiltration by NP-specific, autoaggressive, Cd8 (see 186910) T cells in the pancreas. Rhode et al. (2005) proposed that CXCL10 expression accelerates the autoimmune process by enhancing migration of antigen-specific lymphocytes to their target site.
Wuest and Carr (2008) found that corneal infection with herpes simplex virus-1 (HSV1) resulted in elevated viral titers in the nervous system of Cxcl10 -/- mice, which correlated with defects in leukocyte recruitment to the brainstem. Similar levels of HSV1 were recovered from Cxcl10 -/- or wildtype mice lacking natural killer (NK) cells or virus-specific Cd8-positive T cells. Cxcr3 -/- mice also had poor recruitment of NK cells, but not Cd8-positive cells. Wuest and Carr (2008) concluded that antigen-specific CD8-positive T cells, recruited through CXCL10, are critical in the antiviral response at the brainstem.
Using Ifng-deficient mice and Cxcl10-deficient mice, King et al. (2009) showed that the Ifng-Cxcl10 pathway inhibited abdominal aneurysm formation and promoted plaque formation. They proposed that cellular immunity may play different roles in these 2 vascular diseases.
Blank et al. (2016) found that exposure to synthetic double-stranded RNA, a prototype RNA virus, or recombinant type I IFN (IFNB; 147640) induced cognitive impairment and mood changes in mice. Ifnb activated Ifnar1 (107450) expressed on brain endothelia and epithelia, which released Cxcl10 into brain parenchyma, compromising neuronal function. Mice lacking Cxcl10 or its receptor, Cxcr3, were protected from depressive behavior and impaired learning and memory following Ifnb treatment. Blank et al. (2016) concluded that brain endothelial and epithelial cells play an important role in communication between the central nervous system and the immune system and that IFNAR1 is engaged in a tissue-specific manner during sickness behavior. They proposed that the CXCL10-CXCR3 axis is a target for treatment of behavioral changes during virus infection and type I IFN therapy.
Angiolillo, A. L., Sgadari, C., Taub, D. D., Liao, F., Farber, J. M., Maheshwari, S., Kleinman, H. K., Reaman, G. H., Tosato, G. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J. Exp. Med. 182: 155-162, 1995. [PubMed: 7540647] [Full Text: https://doi.org/10.1084/jem.182.1.155]
Blank, T., Detje, C. N., Speib, A., Hagemeyer, N., Brendecke, S. M., Wolfart, J., Staszewski, O., Zoller, T., Papageorgiou, I., Schneider, J., Paricio-Montesinos, R., Eisel, U. L. M., and 13 others. Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity 44: 901-912, 2016. [PubMed: 27096319] [Full Text: https://doi.org/10.1016/j.immuni.2016.04.005]
Booth, V., Keizer, D. W., Kamphuis, M. B., Clark-Lewis, I., Sykes, B. D. The CXCR3 binding chemokine IP-10/CXCL10: structure and receptor interactions. Biochemistry 41: 10418-10425, 2002. [PubMed: 12173928] [Full Text: https://doi.org/10.1021/bi026020q]
Dufour, J. H., Dziejman, M., Liu, M. T., Leung, J. H., Lane, T. E., Luster, A. D. IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J. Immun. 168: 3195-3204, 2002. [PubMed: 11907072] [Full Text: https://doi.org/10.4049/jimmunol.168.7.3195]
Feferman, T., Maiti, P. K., Berrih-Aknin, S., Bismuth, J., Bidault, J., Fuchs, S., Souroujon, M. C. Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis. J. Immun. 174: 5324-5331, 2005. [PubMed: 15843529] [Full Text: https://doi.org/10.4049/jimmunol.174.9.5324]
Harris, T. H., Banigan, E. J., Christian, D. A., Konradt, C., Tait Wojno, E. D., Norose, K., Wilson, E. H., John, B., Weninger, W., Luster, A. D., Liu, A. J., Hunter, C. A. Generalized Levy walks and the role of chemokines in migration of effector CD8+ T cells. Nature 486: 545-548, 2012. [PubMed: 22722867] [Full Text: https://doi.org/10.1038/nature11098]
King, V. L., Lin, A. Y., Kristo, F., Anderson, T. J. T., Ahluwalia, N., Hardy, G. J., Owens, A. P., III, Howatt, D. A., Shen, D., Tager, A. M., Luster, A. D., Daugherty, A., Gerszten, R. E. Interferon-gamma and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture. Circulation 119: 426-435, 2009. [PubMed: 19139386] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.108.785949]
Luster, A. D., Jhanwar, S. C., Chaganti, R. S. K., Kersey, J. H., Ravetch, J. V. Interferon-inducible gene maps to a chromosomal band associated with a (4;11) translocation in acute leukemia cells. Proc. Nat. Acad. Sci. 84: 2868-2871, 1987. [PubMed: 2437586] [Full Text: https://doi.org/10.1073/pnas.84.9.2868]
Luster, A. D., Unkeless, J. C., Ravetch, J. V. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 315: 672-676, 1985. [PubMed: 3925348] [Full Text: https://doi.org/10.1038/315672a0]
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]
Rhode, A., Pauza, M. E., Barral, A. M., Rodrigo, E., Oldstone, M. B. A., von Herrath, M. G., Christen, U. Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development. J. Immun. 175: 3516-3524, 2005. [PubMed: 16148094] [Full Text: https://doi.org/10.4049/jimmunol.175.6.3516]
Singh, U. P., Singh, S., Taub, D. D., Lillard, J. W., Jr. Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10-/- mice. J. Immun. 171: 1401-1406, 2003. [PubMed: 12874231] [Full Text: https://doi.org/10.4049/jimmunol.171.3.1401]
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]
Wathelet, M. G., Szpirer, J., Nols, C. B., Clauss, I. M., De Wit, L., Islam, M. Q., Levan, G., Horisberger, M. A., Content, J., Szpirer, C., Huez, G. A. Cloning and chromosomal location of human genes inducible by type I interferon. Somat. Cell Molec. Genet. 14: 415-426, 1988. [PubMed: 3175763] [Full Text: https://doi.org/10.1007/BF01534709]
Wuest, T. R., Carr, D. J. J. Dysregulation of CXCR3 signaling due to CXCL10 deficiency impairs the antiviral response to Herpes simplex virus 1 infection. J. Immun. 181: 7985-7993, 2008. [PubMed: 19017990] [Full Text: https://doi.org/10.4049/jimmunol.181.11.7985]
Zhang, R., Zhang, H., Zhu, W., Pardee, A. B., Coffey, R. J., Jr., Liang, P. Mob-1, a Ras target gene, is overexpressed in colorectal cancer. Oncogene 14: 1607-1610, 1997. [PubMed: 9129152] [Full Text: https://doi.org/10.1038/sj.onc.1200957]
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]