CXCL10 (chemokine (C-X-C motif) ligand 10)

2012-05-01   Frank Antonicelli , Philippe Bernard 

Universite de Reims Champagne-Ardenne, Laboratoire de Dermatologie, CNRS FRE-3481, UFR medecine, Reims, France (FA); CHU de Reims, Hopital Robert Debre, Service de Dermatologie, Reims, France (PB)

Identity

HGNC
LOCATION
4q21.1
LOCUSID
ALIAS
C7,IFI10,INP10,IP-10,SCYB10,crg-2,gIP-10,mob-1

DNA/RNA

Note

CXCL10 gene, localized on the chromosome 4 at band q21, was originally described in 1985 by Luster (Luster et al., 1985). The CXCL10 cDNA arises from 4 exons encoding for a 12 kDa protein (Liu et al., 2011; Luster and Ravetch, 1987), which is widely expressed. Transcription CXCL10, also named IP-10 for Interferon-g-inducible protein 10, is induced by a large range of innate and adaptive immune stimuli that induce the production of IFN type-1 and tye-2. Inflammatory stimuli, such as TNFα, have also been shown to induce CXCL10 expression (Nestle et al., 2009; Nakae et al., 2003). The CXCL10 promoter includes response element for Interferon Regulatory Factor (IRF)1 and for many other transcription factor such as NF-κB, STAT-1, AP-1, FoxA2a, FoxF2, FHXA/FHXB-1, FHXA/FHXB-2 and CEBP (Lu et al., 2011; Clarke et al;, 2010). It was shown recently that CXCL10 promoter also contains a Gamma Activating Sequence (GAS) response element that is activated following homodimerisation of phosphorylated STAT1 (Saha et al., 2010). CXCL10 mRNA is stabilized by S100b protein binding at the 3-UTR regions (Shanmugam et al., 2006). Multiple alignment sequences of pig, human, mouse, goat and sheep of CXCL10 gene product shows 86, 74, 72, 82 and 83% of homology respectively (Yang et al., 2007).

Proteins

Atlas Image

Description

The primary translation product corresponds to a protein of 12 kDa that is then limited proteolysed in a protein of 98 amino acids mature protein of 10k Da after release of the signal peptide. The three-dimensional crystal structure of CXCL10 has been determined under different conditions, and the protein structural data have the following accession codes 1lv9, 1o7y, and 1o80 in the Protein Data Bank (Fig. 1). CXCL10 activity is bound to its structure and cleavage by MMPs and x-prolyl dipeptidyl peptidase enzymes. The C-terminal truncation leaves CXCL10 under an active form, whereas reduction of its N-terminal tail generates a dominant negative antagonist. Then determination of the balance between the agonists and the antagonist forms is of interest in monitoring the role of CXCL10 in cancer and inflammatory diseases (Casrouge et al., 2012).

Expression

CXCL10 is secreted by several cell types including T lymphocytes, neutrophils, monocytes, splenocytes, endothelial cells, fibroblasts, keratinocytes, osteoblasts, astrocytes and smooth muscle cells.

Localisation

CXCL10 is a secreted protein present in body fluids and in tissues.

Function

CXCL10 is a pleiotropic molecule that exerts several functions according to the cell type and the CXCL10 receptor isoform they express. The mature form of CXCL10 and two other members of the CXC chemokine family, CXCL9 (Mig) and CXCL11 (I-TAC), bind the CXCR3 receptor, with a higher affinity for the CXCR3A than the CXCR3B isoform. A third isoform of CXCR3 (CXCR3-alt) is always co-expressed at a very low level with CXCR3A, but its function has still not been determined ( Lo et al., 2010; Aksoy et al., 2006). According to cell types and CXCL10 receptors, several signalling pathways can be activated. Following to CXCL10 binding, CXCR3A activates Erk1/2, JNK and PI3K/AKT pathways (Liu et al., 2011; Ji et al., 2008; Maru et al., 2008; Aksoy et al., 2006; Loetscher et al., 1998), while CXCR3B stimulated the adenylyl cyclase cascade and p38/MAPK (Aksoy et al., 2006; Giuliani et al., 2006; Lazzeri and Romagnani, 2005; Romagnani et al., 2005; Kim et al., 2002).

Homology

CXCL10 has significant amino-acid homology to platelet factor-4 and beta-thromboglobulin, two chemotatic proteins released by platelet (Luster et al., 1985).

Implicated in

Entity name
Brain cancer
Note
Using mice models, it has been shown an elevated CXCL10 level upon nonsteroidal anti-inflammatory drugs is associated with enhanced cytotoxic T lymphocytes infiltration and reduced gliomagenesis (Fujita et al., 2011). Accordingly, Glioma-bearing CXCR3-deficient mice had significantly shorter median survival time and reduced numbers of tumor-infiltrated natural killer and natural killer T cells with respect to wild type mice (Liu et al., 2011). In this line, a therapy combining CXCL10 overexpression with glioma lysate-pulsed DCs revealed synergistic effect against glioma progression (Jiang et al., 2009).
Entity name
Breast cancer
Note
In vitro study demonstrated that in breast cancer cells Ras-induced overexpression of CXCL10 is mediated primarily through the Raf and phosphatidylinositol 3-kinase signaling pathways. The expression of the splice variant CXCR3-B, known to inhibit cell proliferation, is significantly down-regulated by Ras, suggesting that CXCL10-mediated breast cancer cell proliferation likely involves CXCR3-A (Datta et al., 2006). Besides, in murine breast cancer CXCL10 impairs tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. In such models, CXCL10 expression is controlled by PGE2 and cyclooxygenase inhibition (Bronger et al., 2012). The anti-tumoral immune response is favored by IFN-γ secreted from NK cells which promotes the production of CXCL10 from breast cancer cells, and in turn accelerates the migration of CXCR3-expressing NK cells into the tumor site. Then, activation of autologous NK cells could represent a potential therapeutic adoptive transfer (Kajitani et al., 2012).
Entity name
Colorectal cancer
Note
Colorectal cancer is a complex disease involving immune defense mechanisms. Data from 108 patients showed that in patients with prolonged disease-free survival, CXCL10 correlated with different subsets of immune cells displaying particular TCR repertoire and with high densities of T-cell subpopulations within specific tumor regions (Mlecnik et al., 2010). Conversely, CXCL10 level increased with advanced colorectal cancer, with vascular invasion and distant metastasis. Then, CXCL10 was associated with poor prognosis and liver metastasis (Toiyama et al., 2012). CXCL10 deleterious effects are triggered by TNFα-induced NF-kB transcriptional activation and can be suppressed by 3-Chloro-5,7-dimethoxyisoflavone, a synthetic isoflavone derivative (Shin et al., 2011).
Entity name
Liver cancer
Note
Among a 14-gene immune signature, CXCL10 contributes at predicting patient survival with hepatocellular carcinoma issued from two series includes, irrespectively of patient ethnicity and disease aetiology. In this study, CXCL10 correlates with markers of T helper 1 (Th1), CD8(+) T and natural killer (NK) cells, and good prognosis for patients with early disease (stages I and II), but not in late disease stages III and IV (Chew et al., 2012). Besides, use of an orthotopic liver tumor nude mice model with distant metastatic potential, adiponectin downregulates the ROCK/IP10/MMP-9 signaling pathway from tumor cell, and inhibits liver tumor growth and metastasis by reducing the formation of lamellipodia, which contribute to cell migration (Man et al., 2010). Of interest, CXCL10 level in different hepatocellular carcinoma cell lines is determined by melatonin concentration, which therefore could present relevant application for patients with hepatocellular carcinoma (Lin and Chuang, 2010). Loss of hepatocyte c-Met receptor causes a strong deregulation of chemotactic and inflammatory signaling such as CXCL10, and alters hepatic microenvironment and aggravated hepatic fibrogenesis (Marquardt et al., 2012).
Entity name
Lung cancer
Note
CXCR3 expression in CD4(+) T cells from pleural plaque and mesothelioma is significantly reduced compared with that from healthy donors, and CD4(+)CXCR3(+) T cells from mesothelioma showed an inverse correlation with its ligand CXCL10/IP10 in plasma. This suggests that CXCR3and CXCL10/IP10 may be candidates to detect and monitor the antitumor immune function in patients with lung cancer and mesothelioma (Maeda et al., 2011). In this respect, although a synergistic antitumor effect is not observed in a combined treatment using CXCL10 and CXCL11, a chimeric molecule engineered by substituting the N-terminal and N-loop region of CXCL10 with those of CXCL11 promotes regression of established tumors and remarkably prolonges survival of mice compared to these chemokines used either alone or in combination (Wang et al., 2010). In this line, a chimeric γc homeostatic cytokine, IL-7/IL-7Rα-Fc promotes afferent and efferent antitumor responses in lung cancer by increasing CXCL10 expression, tumor macrophage infiltrates, frequencies of T and NK cells, effector memory T cells and T cell cytolytic activity against parental tumor cells (Andersson et al., 2011).
Entity name
Lymphoma
Note
CXCL10 was discovered following treatment of a lymphoma cell line (U937) with IFN-γ (Luster et al., 1985). Recently, a prognostic value was attributed to this chemokine in large-cell lymphoma and myelodysplastic syndromes suggesting a deleterious pathogenic contribution of this chemokine in these diseases development (Pardanani et al., 2011). Likewise, CXCL10 has been associated with epidermotropism of cutaneous T-lymphoma cells, which could partly explain the clonal expansion of lymphocytes in the skin in the absence of systemic involvement (Sugaya, 2011).
Entity name
Melanoma
Note
The antitumoral effects of CXCL10 were demonstrated in vivo using different animal models (Antonicelli et al., 2011; Feldman et al., 2002). Notably, it was shown that suppression of melanoma growth by thalidomide was associated with up-regulation of CXCL10 in the spleen of mice (Kawamata et al., 2006). In Human, induction of IP-10/CXCL10 secretion was proposed as an immunomodulatory effect of low-dose adjuvant interferon-alpha during treatment of melanoma (Mohty et al., 2010). High level expression of CXCL10 was detected in situ in regressive human primary melanoma concomitantly with the CXCR3+ lymphocyte recruitment (Wenzel et al., 2005). A high CXCL10 concentration is also secreted by PBMC from patients with melanoma in regression compared to patients with melanoma in progression (Antonicelli et al., 2011). Besides its chemotactic activity, this chemokine interacts either directly with melanoma cells to control tumour progression (Antonicelli et al., 2011) or reduces the microvessel density (Yang and Richmond, 2004).
Entity name
Ovarian cancer
Note
Analysis of 201 ovarian cancer patients revealed that tumor-infiltrating Th17 cells are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. The synergistic action between IL-17 and interferon-gamma, stimulate CXCL9 and CXCL10 production to recruit effector T cells and therefore contribute to protective human tumor immunity (Kryczek et al., 2009). Viral infection increases detection and elimination by immune cells. Viral infection stimulates RNA helicase retinoic acid-inducible gene-I induced CXCL10 from ovarian cancer cells and HLA class I upregulation. These cells become succeptible to apoptosis, phagocytose by monocytes and monocyte-derived dendritic cells, which in turn upregulated HLA class I/II and costimulatory molecules and released CXCL10 and IFN-alpha (Kübler et al., 2010).
Entity name
Prostate cancer
Note
In prostate cancer, CXCL10/IP10 promotes cell motility and invasiveness via PLCβ3 and µ-calpain activation. Meanwhile, CXCR3A mRNA level is upregulated while CXCR3B mRNA is downregulated in these prostate cancer specimens (Wu et al., 2012). However, in invitro study showed that CXCL10 inhibits prostate cancer cell proliferation and decreased PSA production by up-regulation of CXCR3 receptor suggesting that CXCL10 may be potentially useful in the treatment of prostate cancer (Nagpal et al., 2006). In this line, neoadjuvant hormone therapy boosts the expression CXCL10 in the glandular epithelium of normal prostate tissue, and restored the CD8(+) lymphocyte depletion occurring in prostate cancer, whereas it significantly increased the CD4(+) lymphocyte infiltrate. However, it also increased the number of T regulatory cells, and then might have no impact on disease free survival (Sorrentino et al., 2011).
Entity name
Immunity
Note
Peripheral inflammatory markers are often used as predictor of tumour development. Determination of high level of CXCL10 in peripheral liquids is therefore a marker of host immune response, especially Th1 orientated T-cells, which have been shown to be associated with a better prognosis for many cancer types including brain (Elstner et al., 2011; Okada, 2009), hepatic (Moura et al., 2009) and colorectal (Engel and Neurath, 2010) neoplasms, or melanoma (Antonicelli et al., 2011; Mohty et al., 2010). In this line, natural Killer lymphocytes endowed immunoregulatory functions by secreting IFN-γ. Therefore these cells have been successfully employed to treat patients with myeloid leukaemia and other haematological malignancies (Maghazachi, 2010). Animal model showed apparent overexpression in tissue with tumour undergoing regression reflecting an immune host response (Tosato et al., 1998). Similarly, expression of CXCL10 as determined by immunocytochemistry was increased in tumour skin frozen sections (Daliani et al., 1998). Increased CXCL10 expression at site of injury could enhance the homing of immune cells expression the CXCR3 receptor (Okada, 2009). Recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop (Antonelli et al., 2008). This chemotactic-based amplification loop is impaired when the NH-2 terminal CXCL10 extremity is truncated (Persano et al., 2011; Proost et al., 2001). Although such sustained inflammatory and immune response is of interest to reduce tumour progression, it also may predispose or lead to autoimmune disorders (Lacotte et al., 2009; Antonelli et al., 2008; Liu et al., 2008; Luster et al., 1985).
Entity name
Angiostasis
Note
As an ELR- CXC chemokine, CXCL10 displays angiostatic effects through binding to its CXCR3B receptor subunit. This anti-angiogenic effect is processed through inhibition of proliferation and induction of apoptosis of endothelial cells (Liu et al., 2011; Feldman et al., 2006). These effects are mediated by a downstream CXCR3B activation of the p38 pathway (Petrai et al., 2008). CXCL10 also antagonizes the pro-angiogenic effects of bFGF and VEGF (Aronica et al., 2009; Sato et al., 2007). Of note, the NH-2 CXCL10 truncation impaired its signalling cascade effects with modifying its anti-angiogenic properties (Struyf et al., 2011; Proost et al., 2001). Consequently, CXCL10 level has been inversely correlated with tumour progression such as in lymphoma, squamous cells carcinoma, carcinoma, melanoma and many others tumour types. However, preclinical studies have clearly indicated that such cytostatic factor need long-term administration to display an antitumoral effect, which furthermore is only really efficient during the early phase of tumour progression (Persano et al., 2007).

Bibliography

Pubmed IDLast YearTitleAuthors
163397792006CXCR3 surface expression in human airway epithelial cells: cell cycle dependence and effect on cell proliferation.Aksoy MO et al
216365532011Role of CXCR3 ligands in IL-7/IL-7R alpha-Fc-mediated antitumor activity in lung cancer.Andersson A et al
187081692008Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia.Antonelli A et al
211557502011CXCL10 reduces melanoma proliferation and invasiveness in vitro and in vivo.Antonicelli F et al
190143402009Antitumor/antiestrogenic effect of the chemokine interferon inducible protein 10 (IP-10) involves suppression of VEGF expression in mammary tissue.Aronica SM et al
109144832000CXC chemokines in angiogenesis.Belperio JA et al
223333152012Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer.Bronger H et al
221328932012Discrimination of agonist and antagonist forms of CXCL10 in biological samples.Casrouge A et al
219307322012Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma.Chew V et al
208337302010TNFα and IFNγ synergistically enhance transcriptional activation of CXCL10 in human airway smooth muscle cells via STAT-1, NF-κB, and the transcriptional coactivator CREB-binding protein.Clarke DL et al
96849291998Tumor necrosis factor-alpha and interferon-gamma, but not HTLV-I tax, are likely factors in the epidermotropism of cutaneous T-cell lymphoma via induction of interferon-inducible protein-10.Daliani D et al
170186072006Ras-induced modulation of CXCL10 and its receptor splice variant CXCR3-B in MDA-MB-435 and MCF-7 cells: relevance for the development of human breast cancer.Datta D et al
206173652011Identification of diagnostic serum protein profiles of glioblastoma patients.Elstner A et al
207125742010Anticancer properties of the IL-12 family--focus on colorectal cancer.Engel MA et al
119485062002Retroviral gene transfer of interferon-inducible protein 10 inhibits growth of human melanoma xenografts.Feldman AL et al
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213249232011COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells.Fujita M et al
170820082006CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival.Giuliani N et al
183757412008Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A.Ji R et al
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222619322012Mechanistic analysis of the antitumor efficacy of human natural killer cells against breast cancer cells.Kajitani K et al
170890432006Thalidomide suppresses melanoma growth by activating natural killer cells in mice.Kawamata A et al
123702712002Inhibition of endothelial cell survival and angiogenesis by protein kinase A.Kim S et al
194706942009Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments.Kryczek I et al
205510642010Targeted activation of RNA helicase retinoic acid-inducible gene-I induces proimmunogenic apoptosis of human ovarian cancer cells.Kübler K et al
197581672009CXCR3, inflammation, and autoimmune diseases.Lacotte S et al
157772092005CXCR3-binding chemokines: novel multifunctional therapeutic targets.Lazzeri E et al
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Other Information

Locus ID:

NCBI: 3627
MIM: 147310
HGNC: 10637
Ensembl: ENSG00000169245

Variants:

dbSNP: 3627
ClinVar: 3627
TCGA: ENSG00000169245
COSMIC: CXCL10

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000169245ENST00000306602P02778
ENSG00000169245ENST00000306602A0A024RDA4

Expression (GTEx)

0
5
10
15

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Toll-like receptor signaling pathwayKEGGko04620
Cytokine-cytokine receptor interactionKEGGhsa04060
Toll-like receptor signaling pathwayKEGGhsa04620
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
Cytosolic DNA-sensing pathwayKEGGko04623
Cytosolic DNA-sensing pathwayKEGGhsa04623
Influenza AKEGGko05164
Influenza AKEGGhsa05164
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
Chemokine receptors bind chemokinesREACTOMER-HSA-380108
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (i) signalling eventsREACTOMER-HSA-418594
Interleukin-10 signalingREACTOMER-HSA-6783783
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164749390peginterferon alfa-2aChemicalClinicalAnnotationassociatedPD
PA164784024peginterferon alfa-2bChemicalClinicalAnnotationassociatedPD
PA446863Hepatitis C, ChronicDiseaseClinicalAnnotationassociatedPD

References

Pubmed IDYearTitleCitations
159443272005Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity.231
218023432011CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications.159
129492492003Many chemokines including CCL20/MIP-3alpha display antimicrobial activity.154
159199352005Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis.131
120161042002Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease.88
151502612004Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function.85
158794272005The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle.82
187983342008Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.81
231443312013CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin.73
167336542006Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis.70

Citation

Frank Antonicelli ; Philippe Bernard

CXCL10 (chemokine (C-X-C motif) ligand 10)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: http://atlasgeneticsoncology.org/gene/40218/cxcl10-(chemokine-(c-x-c-motif)-ligand-10)