IP-10 Andrew D. Luster * Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA *corresponding author tel: 617-726-5710, fax: 617-726-5411, e-mail: [email protected] DOI: 10.1006/rwcy.2000.10007. SUMMARY Structure IP-10 is a CXC chemokine that is induced from most IP-10 is a 77 amino acid secreted nonglycosylated cells in response to both type I and type II interferon protein (Luster and Ravetch, 1987a). It contains four stimulation and LPS. IP-10 is chemotactic for cysteines in the mature protein with the first two activated T cells and NK cells by binding to and cysteines separated by an amino acid. IP-10 lacks the activatingCXCR3.IP-10alsohasantiangiogenicand ELR sequence preceding the first cysteine typical of antitumor activity in vivo. IP-10 expression has been IL-8 and other CXC chemokines active on neutro- seeninmanyTH1-typehumaninflammatorydiseases phils,andhenceitisamemberofthenon-ELRCXC and plays an important role in recruiting activated chemokine family. The N-terminus of IP-10 has been effector T cells into sites of tissue inflammation. identified as valine from protein purified from endothelial cells (Luster and Ravetch, 1987a) and tumorcells(Proostetal.,1993)andIP-10isknownto BACKGROUND be biologically active in this form. IP-10 is a basic proteinandbindsheparinwithrelativelyhighaffinity Discovery (25nM) (Luster et al., 1995). Human IP-10 was discovered as an mRNA that was highlyinducedinthehumanmonocyticcelllineU937 Main activities and by IFN(cid:13) using differential colony hybridization pathophysiological roles (Luster et al., 1985). This mRNA encoded a 10kDa proteinandwasthereforenamedIP-10forinterferon- IP-10ischemotacticforactivatedTcellsandNKcells inducibleproteinof10kDa.Usingasimilarapproach, (Maghazachi et al., 1997; Taub et al., 1993). IP-10 is mouse IP-10 was independently discovered by two thoughttoplayanimportantroleinrecruitingTcells, groups as a gene induced in monocytes by activated activated in regional lymph nodes, into sites of T cell supernatants (Vanguri and Farber, 1990) and inflammationandinfection.IP-10alsoinhibitsangio- byLPS(OhmoriandHamilton,1990).RatIP-10was genesis and tumor growth in vivo (Luster and Leder, identified as a gene induced in fibroblasts by trans- 1993; Angiolillo et al., 1995; Luster et al., 1995; formation with Ha-ras and p53 (Liang et al., 1994) Arenberg et al., 1996). andindependentlyidentifiedasanmRNAinducedin LPS-stimulated carotid arteries (Wang et al., 1996). Alternative names GENE AND GENE REGULATION Accession numbers When they were identified, mouse IP-10 was called crg-2 (Vanguri and Farber, 1990) and rat IP-10 was called mob-1 (Liang et al., 1994). The gene name is Human: X02530 SCYB10 and the consensus nomenclature name is Mouse: M33266, M86829 CXCL10. Rat: U17035, U22520 1104 Andrew D. Luster Chromosome location Figure 1 Amino acid sequence for human IP-10. MNQTAILICC LIFLTLSGIQ GVPLSRTVRC TCISISNQPV NPRSLEKLEI The human IP-10 gene was mapped to 4q21.2 by IPASQFCPRV EIIATMKKKG EKRCLNPESK AIKNLLKAVS KEMSKRSP insituhybridization(Lusteretal.,1987).MouseIP-10 was mapped to chromosome 5. Sequence Relevant linkages See Figure 1 An analysis of P1 clones revealed that IP-10 is linked head to tail to MIG, another non-ELR CXC Description of protein chemokine with which it shares 37% identity, with theirstartcodonsseparatedby<16kb(Farber,1997). The IP-10 cDNA is predicted to encode a protein of 98 amino acids, M 10,855, with a 21 amino acid r leader sequence. Following signal peptidase cleavage, Regulatory sites and corresponding IP-10issecretedasa77aminoacidprotein,M 8620, r transcription factors containing an N-terminal valine. The mature protein has a pI of 10.5. Upstream regions of human and murine IP-10 contain conserved regulatory motifs, including an Discussion of crystal structure IFN-stimulated response element (ISRE) and two NF(cid:20)B sites (Luster and Ravetch, 1987b; Ohmori and The crystal structure has not been determined. Hamilton, 1993). Transcription factors that mediate IP-10 induction are the p48 ISRE-binding protein, Important homologies STAT1a, and p65 homodimeric or p50/p65 hetero- dimeric NF(cid:20)B (Majumder et al., 1998). IP-10 shares (cid:24)37% identity with MIG and I-TAC, two IFN(cid:13)-inducible non-ELR CXC chemokines that Cells and tissues that express chemoattractactivatedTcellsthroughCXCR3.MIG the gene also shares the ability to inhibit angiogenesis in vivo with IP-10. Constitutive IP-10 expression is seen at low levels Posttranslational modifications predominately in the thymus and spleen (Gattass et al., 1994).IP-10 expression hasbeen seenin awide variety of tissues following an infectious or inflam- IP-10 has been purified from a human osteosar- matory stimulus (Farber, 1990). These tissues include coma line containing the mature N-terminus the brain, eye, lung, lymph nodes, intestine, liver, VPLSRTVRCTC... as well as three N-terminally heart, blood vessel, and muscle. Most cell types are processed forms beginning with SRTVRCTC..., able to induce the expression of IP-10 in response to RTVRCTC...,andTVRCTCN(Proostetal.,1993). interferon stimulation, including endothelial cells, The biological significance of these N-terminally keratinocytes, monocytes, respiratory and intestinal truncated forms is not known. epithelial cells, astrocytes, microglia, mesangial cells, and smooth muscle cells. CELLULAR SOURCES AND TISSUE EXPRESSION PROTEIN Cellular sources that produce Accession numbers Many different cell types have been shown to SwissProt: secrete IP-10 upon IFN or LPS stimulation. These Human: P02278 include endothelial cells, keratinocytes, monocytes, Mouse: P17515 respiratory and intestinal epithelial cells, astrocytes, Rat: P48973 microglia, mesangial cells, smooth muscle cells IP-10 1105 (Table 1). The cyclopentenone prostaglandin 15 RECEPTOR UTILIZATION deoxy(cid:255)(cid:1)12,14 prostaglandin J (PGJ ), as well as 2 2 other peroxisone proliferator- activated receptor IP-10 binds to and activates CXCR3, a property it gamma (PPAR(cid:13)) agonists, such as troglitazone and shares with MIG and I-TAC (Loetscher et al., 1996; rosiglitazone, inhibit IFN(cid:13) induction of IP-10 in Qinetal.,1998).IP-10alsobindstoproteoglycanson endothelial cells (Marx et al., 2000). Likewise, nitric endothelial cells (Luster et al., 1995). IP-10 binds to oxide (NO) also inhibits IFN(cid:13) induction of IP-10 in and inhibits the constitutively active G protein- endothelial cells (Mach et al., 1999). coupled receptor ORF 74 encoded by the Kaposi’s sarcoma-associated herpesvirus KSHV8 (Geras- Raaka et al., 1998; Rosenkilde et al., 1999). Eliciting and inhibitory stimuli, including exogenous and endogenous modulators IN VITRO ACTIVITIES Type I (IFN(cid:11)/(cid:12)) and type II (IFN(cid:13)) interferons are In vitro findings potent inducers of IP-10 in vitro and in vivo (Luster etal.,1985;Narumietal.,1992).LPSalsoinducesIP- See Table 2. 10expressioninvivoandinmacrophagesinvitroLPS may induce IP-10 expression through the release of IFN(cid:11)/(cid:12)frommacrophages(Teboetal.,1998).Tcells have also been shown to induce IP-10 expression Table 2 Biological activities of IP-10 following activation with anti-CD3 (Gattass et al., 1994). In vitro TNF, CD40, and IL-1 have been shown to Chemoattracts activated T cells preferentially synergize with IFN(cid:13) in inducing IP-10, especially in CD4+ TH1 and CD8+ cellsthathaveasmallresponsetoIFN(cid:13) alone(Mach Cytotoxic etal., 1999;Sautyet al.,1999).IL-10hasbeenshown to inhibit LPS but not IFN(cid:13) or IFN(cid:11)/(cid:12) induction of Chemoattracts activated NK cells IP-10 transcription or mRNA accumulation (Tebo Chemotactic vascular smooth muscle cells et al., 1998). Induces activated T cell adhesion to VCAM and ICAM Table 1 Cellular source and stimulusa Augments IFN(cid:13) production from CD4+ TH1 lymphocytes Cellular source Stimulusa Mitogenic vascular smooth muscle cells Inhibits IL-8-, FGF- and VEGF-induced chemotaxis of Monocytes/macrophages/ IFN(cid:13), IFN(cid:11)/(cid:12), LPS, endothelial cells microglia viral infection, Inhibits FGF-induced endothelial capillary poly (rI)-poly (rC) tube formation Epithelial cells IFN(cid:13) Inhibits FGF-mediated endothelial cell proliferation Endothelial cells IFN(cid:13), IFN(cid:11)/(cid:12) Inhibits Kaposi’s sarcoma-associated herpes Keratinocytes IFN(cid:13) G protein-coupled receptor in cells T cells Anti-CD3 Inhibition of cytokine-stimulated hematopoietic progenitor cell proliferation Neutrophils IFN(cid:13) Astrocytes IFN(cid:13), TNF(cid:11) In vivo Smooth muscle cells IFN(cid:13), LPS Inhibits tumor growth and metastasis Mesothelial cells IFN(cid:13) Inhibits FGF-induced angiogenesis Fibroblasts IFN(cid:13), IFN(cid:11), TNF(cid:11), Chemoattracts human T cells in SCID mouse model poly (rI)-poly (rC) Overproduction in the skin inhibits wound healing Hepatocytes IFN(cid:13), IFN(cid:11) Required for survival following Toxoplasma gondii infection aTNF,IL-1,CD40ligand,hyaluronanallsynergizewithIFN(cid:13) Controls effector T cell trafficking toinduceIP-10mRNAaccumulationandproteinsecretion. 1106 Andrew D. Luster T Cell Chemotaxis Knockout mouse phenotypes IP-10 induces the chemotaxis of activated peripheral bloodTcells, butnotrestingT cells(Loetscheret al., IP-10 knockouts are viable but no other information 1996). IP-10 acts on CD4+ and CD8+ cells, and about their phenotype is known. will preferentially chemoattract TH1 lymphocytes (Bonecchi et al., 1998; Sallusto et al., 1998). IP-10 is Transgenic overexpression also chemotactic for activated NK cells (Maghazachi et al., 1997). Transgenic mice constitutively expressing IP-10 driven by bovine keratin 5 and 10 promotors have T Cell Adhesion been generated (Luster et al., 1998). These mice had In a static adhesion assay, IP-10 has been shown to impaired wound healing with a delay in the formation inducetheadhesionofactivatedTcellstoICAMand ofneovesselsintheareaofinjury.Thesemicedidnot VCAM (Piali et al., 1998). spontaneously recruit T cells into the skin and had a normal contact hypersensitivity response. Inhibition of FGF-Induced Endothelial Proliferation At high concentrations, IP-10 inhibits the proli- Interactions with cytokine network feration of FGF-stimulated human umbilical cord endothelial cells (Luster et al., 1995; Strieter et al., IP-10has been shown to augment IFN(cid:13) butnot IL-4 1995). production in splenocyte cultures, thus creating an autocrine positive feedback loop that may amplify a Inhibition of FGF- and IL-8-induced chemotaxis TH1 response (Gangur et al., 1998). IP-10 has also been shown to suppress the synergistic action of IP-10 has been shown to inhibit endothelial cell combinations of stimulatory cytokines on hemato- chemotaxis induced by IL-8, FGF, and VGEF poietic progenitor cell growth (Sarris et al., 1993). (Arenberg et al., 1997) and FGF-induced capillary tube formation (Angiolillo et al., 1995). Bioassays used PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND Chemotaxis, calcium flux, and cell adhesion assays DISEASE STATES AND are the predominant assays used for T cells. Cell DIAGNOSTIC UTILITY growth assays and in vivo angiogenesis assays have been used for endothelial cells, and hematopoietic Normal levels and effects progenitor assays for stem cells. ConstitutiveexpressionofIP-10mRNAisseeninthe thymus, spleen and lymph nodes, the function of IN VIVO BIOLOGICAL which is not known (Gattass et al., 1994). ACTIVITIES OF LIGANDS IN ANIMAL MODELS Role in experiments of nature and Normal physiological roles disease states IP-10 appears to be important for the trafficking of IP-10 mRNA and protein are dramatically upregu- activated T cells into sites of inflammation and lated in diseased tissue in a wide variety of disease infection (Table 2). states(Table3)predominantlycharacterizedbyTH1- typeinflammation,includingpsoriasis(Gottliebetal., 1988), sarcoidosis (Agostini et al., 1998), athero- Species differences sclerosis (Mach et al., 1999) multiple sclerosis (Sorensen et al., 1999), leprosy (Kaplan et al., 1987), Human and mouse IP-10 are functional across tuberculosis (Sauty et al., 1999), and glomerulo- species. nephritis. IP-10 is also profoundly induced in murine IP-10 1107 Table 3 Expression of IP-10 in human diseases and animal models of disease Human diseases Animal models Multiple sclerosis Experimental allergic encephalomyelitis Sarcoidosis Experimental tubulointerstitial nephritis Psoriasis Antiglomerular basement membrane glomerulonephritis Glomerulonephritis Experimental nephrosis Atherosclerosis Plasmodium yoelli Pulmonary tuberculosis Mycobacterium tuberculosis Lepromatous leprosy Mouse hepatitis Viral meningitis Lymphocytic choriomeningitis Fixed drug eruption Newcastle disease Wound healing Vaccina virus Chronic active hepatitis Toxoplasma gondii HIV encephalitis SIV encephalitis Pulmonary fibrosis Bleomycin-induced lung injury Organ transplantation Organ transplantation Uveitis Listeriosis Cutaneous T cell lymphomas Models acute respiratory distress syndrome Hypoxic and traumatic organ injury models following infection with Toxoplasma gondii mumigandcrg-2areinducedinprotozoanandviralinfections (Amichayetal.,1996;Khanetal.,2000),Plasmodium in response to IFN-(cid:13) with patterns of tissue expression that suggest nonredundant roles in vivo. 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