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Gene Review

CXCR3  -  chemokine (C-X-C motif) receptor 3

Homo sapiens

Synonyms: C-X-C chemokine receptor type 3, CD182, CD183, CKR-L2, CMKAR3, ...
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Disease relevance of CXCR3


Psychiatry related information on CXCR3


High impact information on CXCR3

  • In addition, PDCs down-regulate CXCR3 and L-selectin, which mediate migration and homing of these cells into the lymph node [7].
  • The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 [8].
  • An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4 [9].
  • Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation [8].
  • These multiple activities are apparently mediated by a unique G protein-coupled receptor, termed CXCR3 [9].

Chemical compound and disease context of CXCR3


Biological context of CXCR3

  • We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection [15].
  • Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4 [9].
  • CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis [16].
  • In this study, we performed an extensive mutational analysis to identify the CXCR3 and heparin binding sites of murine IP-10 [17].
  • This correlated with studies using recombinant chemokines, which revealed that I-TAC was the most potent inducer of CXCR3 down-regulation and of transendothelial migration [18].

Anatomical context of CXCR3

  • When polarized T cell lines were analyzed, CXCR3 was found to be expressed at high levels on T helper cell (Th)0s and Th1s and at low levels on Th2s [19].
  • We also report that the CXCR3 ligand, Mig, is coexpressed on tumor cells in many cases of CLL/SLL (10 of 13 cases examined) with Mig expression less frequently seen in other B-cell lymphoma subtypes [1].
  • CXCR3 is a G-protein-coupled seven-transmembrane domain chemokine receptor that plays an important role in effector T-cell and NK cell trafficking [16].
  • We report the novel finding that CXCR3 is also expressed on CD34(+) hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34(+) progenitors [20].
  • In vitro, HepG2 cells secreted functional chemotactic factors for tumor-derived lymphocytes that could be inhibited using anti-CCR5 or anti-CXCR3 monoclonal antibodies (MoAbs) [21].

Associations of CXCR3 with chemical compounds

  • Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection [15].
  • Mutations of charged and uncharged residues in the loop regions of residues 20-24 and 46-47, which caused reduced heparin binding, also resulted in reduced CXCR3 binding and signaling [17].
  • The functionality of chemokine receptors CCR5 and CXCR3 on gammadelta T cells was demonstrated by Ca(2+) mobilization and chemotactic response to the respective chemokines [22].
  • The N-terminal residue Arg-8, preceding the first cysteine, was critical for CXCR3 signaling [17].
  • Here, we investigated the capacity of CXCR3 ligands to modulate allergen-driven IFNgamma production by healthy and allergic individuals characterized by Th1 and Th2 immunity-dominated allergen specific responses, respectively [23].

Physical interactions of CXCR3

  • NMR structure of CXCR3 binding chemokine CXCL11 (ITAC) [24].
  • Truncated CXCL11 [CXCL11(3-73)] had an eightfold reduced potential to bind and to regulate CXCR3, but was completely inactive in calcium flux and chemotaxis assays [25].
  • NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors [26].
  • A CXCR3 variant carrying the CXCR4 binding pocket was constructed by simultaneous lysine-to-alanine and serine-to-glutamate substitutions at positions 300 and 304 of the CXCR3 receptor [27].

Regulatory relationships of CXCR3

  • The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects) [28].
  • A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan [29].
  • These results suggest that chemokines that attract Th1 cells via CXCR3 can concomitantly block the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of T cell recruitment [30].
  • Infiltrating T cells around high endothelial venules in RA synovium and 90 +/- 3% of SF CD3(+)CD4(+) T cells expressed CXCR3, and 85 +/- 2% of SF CD3(+)CD4(+) T cells expressed CCR5 [31].
  • After activation, 84% of PBLs expressed CCR5, 90% expressed CXCR3 and 19% expressed CX3CR1 [32].
  • These data suggest that IKK2 is also involved in the IFN-gamma-stimulated release of the CXCR3 ligands through a novel mechanism that is independent NF-kappaB [33].

Other interactions of CXCR3

  • The chemotactic activity of the Mtb-infected DC supernatants was evaluated by migration assays using activated NK, CD4(+), and CD8(+) cells that expressed both CCR5 and CXCR3 [34].
  • While studying responses that are mediated by these two receptors, we found that the agonists for CXCR3 act as antagonists for CCR3 [30].
  • Following in vitro activation of purified CD4 T cells, only CCR2 was internalized, whereas expression of CXCR3 was retained in activated CD4 cells [35].
  • In addition, radiolabeled human 6Ckine does not bind to either human CXCR3 or mouse CXCR3 [36].
  • Eotaxin, therefore, may be a natural CXCR3 antagonist [37].

Analytical, diagnostic and therapeutic context of CXCR3


  1. The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. Jones, D., Benjamin, R.J., Shahsafaei, A., Dorfman, D.M. Blood (2000) [Pubmed]
  2. Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes. Kawada, K., Sonoshita, M., Sakashita, H., Takabayashi, A., Yamaoka, Y., Manabe, T., Inaba, K., Minato, N., Oshima, M., Taketo, M.M. Cancer Res. (2004) [Pubmed]
  3. Ras-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., Flaxenburg, J.A., Laxmanan, S., Geehan, C., Grimm, M., Waaga-Gasser, A.M., Briscoe, D.M., Pal, S. Cancer Res. (2006) [Pubmed]
  4. Neuronal apoptosis is mediated by CXCL10 overexpression in simian human immunodeficiency virus encephalitis. Sui, Y., Potula, R., Dhillon, N., Pinson, D., Li, S., Nath, A., Anderson, C., Turchan, J., Kolson, D., Narayan, O., Buch, S. Am. J. Pathol. (2004) [Pubmed]
  5. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease. Xia, M.Q., Bacskai, B.J., Knowles, R.B., Qin, S.X., Hyman, B.T. J. Neuroimmunol. (2000) [Pubmed]
  6. Serum IFN-inducible protein-10: a new clinical prognostic predictor of hepatocyte death in biliary atresia. Kobayashi, H., Narumi, S., Tamatani, T., Lane, G.J., Miyano, T. J. Pediatr. Surg. (1999) [Pubmed]
  7. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Cella, M., Facchetti, F., Lanzavecchia, A., Colonna, M. Nat. Immunol. (2000) [Pubmed]
  8. The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. Vanbervliet, B., Bendriss-Vermare, N., Massacrier, C., Homey, B., de Bouteiller, O., Brière, F., Trinchieri, G., Caux, C. J. Exp. Med. (2003) [Pubmed]
  9. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. Lasagni, L., Francalanci, M., Annunziato, F., Lazzeri, E., Giannini, S., Cosmi, L., Sagrinati, C., Mazzinghi, B., Orlando, C., Maggi, E., Marra, F., Romagnani, S., Serio, M., Romagnani, P. J. Exp. Med. (2003) [Pubmed]
  10. Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. Flier, J., Boorsma, D.M., van Beek, P.J., Nieboer, C., Stoof, T.J., Willemze, R., Tensen, C.P. J. Pathol. (2001) [Pubmed]
  11. Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris. Rottman, J.B., Smith, T.L., Ganley, K.G., Kikuchi, T., Krueger, J.G. Lab. Invest. (2001) [Pubmed]
  12. Periplocoside E inhibits experimental allergic encephalomyelitis by suppressing interleukin 12-dependent CCR5 expression and interferon-gamma-dependent CXCR3 expression in T lymphocytes. Zhu, Y.N., Zhong, X.G., Feng, J.Q., Yang, Y.F., Fu, Y.F., Ni, J., Liu, Q.F., Tang, W., Zhao, W.M., Zuo, J.P. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  13. Autoantigens act as tissue-specific chemoattractants. Oppenheim, J.J., Dong, H.F., Plotz, P., Caspi, R.R., Dykstra, M., Pierce, S., Martin, R., Carlos, C., Finn, O., Koul, O., Howard, O.M. J. Leukoc. Biol. (2005) [Pubmed]
  14. A Novel CCR5/CXCR3 Antagonist Protects Intestinal Ischemia/Reperfusion Injury. Akahori, T., Sho, M., Kashizuka, H., Nomi, T., Kanehiro, H., Nakajima, Y. Transplant. Proc. (2006) [Pubmed]
  15. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. Hancock, W.W., Lu, B., Gao, W., Csizmadia, V., Faia, K., King, J.A., Smiley, S.T., Ling, M., Gerard, N.P., Gerard, C. J. Exp. Med. (2000) [Pubmed]
  16. CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis. Colvin, R.A., Campanella, G.S., Manice, L.A., Luster, A.D. Mol. Cell. Biol. (2006) [Pubmed]
  17. CXCR3 and heparin binding sites of the chemokine IP-10 (CXCL10). Campanella, G.S., Lee, E.M., Sun, J., Luster, A.D. J. Biol. Chem. (2003) [Pubmed]
  18. CXCR3 internalization following T cell-endothelial cell contact: preferential role of IFN-inducible T cell alpha chemoattractant (CXCL11). Sauty, A., Colvin, R.A., Wagner, L., Rochat, S., Spertini, F., Luster, A.D. J. Immunol. (2001) [Pubmed]
  19. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. Sallusto, F., Lenig, D., Mackay, C.R., Lanzavecchia, A. J. Exp. Med. (1998) [Pubmed]
  20. CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma-inducible protein 10 and monokine induced by interferon gamma. Jinquan, T., Quan, S., Jacobi, H.H., Jing, C., Millner, A., Jensen, B., Madsen, H.O., Ryder, L.P., Svejgaard, A., Malling, H.J., Skov, P.S., Poulsen, L.K. Blood (2000) [Pubmed]
  21. Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. Yoong, K.F., Afford, S.C., Jones, R., Aujla, P., Qin, S., Price, K., Hubscher, S.G., Adams, D.H. Hepatology (1999) [Pubmed]
  22. Patterns of chemokine receptor expression on peripheral blood gamma delta T lymphocytes: strong expression of CCR5 is a selective feature of V delta 2/V gamma 9 gamma delta T cells. Glatzel, A., Wesch, D., Schiemann, F., Brandt, E., Janssen, O., Kabelitz, D. J. Immunol. (2002) [Pubmed]
  23. Allergic humans are hyporesponsive to a CXCR3 ligand-mediated Th1 immunity-promoting loop. Campbell, J.D., Gangur, V., Simons, F.E., HayGlass, K.T. FASEB J. (2004) [Pubmed]
  24. NMR structure of CXCR3 binding chemokine CXCL11 (ITAC). Booth, V., Clark-Lewis, I., Sykes, B.D. Protein Sci. (2004) [Pubmed]
  25. Dipeptidyl peptidase IV (CD26) on T cells cleaves the CXC chemokine CXCL11 (I-TAC) and abolishes the stimulating but not the desensitizing potential of the chemokine. Ludwig, A., Schiemann, F., Mentlein, R., Lindner, B., Brandt, E. J. Leukoc. Biol. (2002) [Pubmed]
  26. Pharmacological characterization of CXC chemokine receptor 3 ligands and a small molecule antagonist. Heise, C.E., Pahuja, A., Hudson, S.C., Mistry, M.S., Putnam, A.L., Gross, M.M., Gottlieb, P.A., Wade, W.S., Kiankarimi, M., Schwarz, D., Crowe, P., Zlotnik, A., Alleva, D.G. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  27. Modest human immunodeficiency virus coreceptor function of CXCR3 is strongly enhanced by mimicking the CXCR4 ligand binding pocket in the CXCR3 receptor. Hatse, S., Huskens, D., Princen, K., Vermeire, K., Bridger, G.J., De Clercq, E., Rosenkilde, M.M., Schwartz, T.W., Schols, D. J. Virol. (2007) [Pubmed]
  28. Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. Lohmann, T., Laue, S., Nietzschmann, U., Kapellen, T.M., Lehmann, I., Schroeder, S., Paschke, R., Kiess, W. Diabetes (2002) [Pubmed]
  29. A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan. Soejima, K., Rollins, B.J. J. Immunol. (2001) [Pubmed]
  30. The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3. Loetscher, P., Pellegrino, A., Gong, J.H., Mattioli, I., Loetscher, M., Bardi, G., Baggiolini, M., Clark-Lewis, I. J. Biol. Chem. (2001) [Pubmed]
  31. CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Patel, D.D., Zachariah, J.P., Whichard, L.P. Clin. Immunol. (2001) [Pubmed]
  32. Chemoattraction of T cells expressing CCR5, CXCR3 and CX3CR1 by proximal tubular epithelial cell chemokines. Cockwell, P., Calderwood, J.W., Brooks, C.J., Chakravorty, S.J., Savage, C.O. Nephrol. Dial. Transplant. (2002) [Pubmed]
  33. The role of IkappaB kinase 2, but not activation of NF-kappaB, in the release of CXCR3 ligands from IFN-gamma-stimulated human bronchial epithelial cells. Tudhope, S.J., Catley, M.C., Fenwick, P.S., Russell, R.E., Rumsey, W.L., Newton, R., Barnes, P.J., Donnelly, L.E. J. Immunol. (2007) [Pubmed]
  34. IFN-alpha beta released by Mycobacterium tuberculosis-infected human dendritic cells induces the expression of CXCL10: selective recruitment of NK and activated T cells. Lande, R., Giacomini, E., Grassi, T., Remoli, M.E., Iona, E., Miettinen, M., Julkunen, I., Coccia, E.M. J. Immunol. (2003) [Pubmed]
  35. Roles of CCR2 and CXCR3 in the T cell-mediated response occurring during lupus flares. Amoura, Z., Combadiere, C., Faure, S., Parizot, C., Miyara, M., Raphaël, D., Ghillani, P., Debre, P., Piette, J.C., Gorochov, G. Arthritis Rheum. (2003) [Pubmed]
  36. Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors. Jenh, C.H., Cox, M.A., Kaminski, H., Zhang, M., Byrnes, H., Fine, J., Lundell, D., Chou, C.C., Narula, S.K., Zavodny, P.J. J. Immunol. (1999) [Pubmed]
  37. Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. Weng, Y., Siciliano, S.J., Waldburger, K.E., Sirotina-Meisher, A., Staruch, M.J., Daugherty, B.L., Gould, S.L., Springer, M.S., DeMartino, J.A. J. Biol. Chem. (1998) [Pubmed]
  38. CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis. Segerer, S., Banas, B., Wörnle, M., Schmid, H., Cohen, C.D., Kretzler, M., Mack, M., Kiss, E., Nelson, P.J., Schlöndorff, D., Gröne, H.J. Am. J. Pathol. (2004) [Pubmed]
  39. Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis. Feferman, T., Maiti, P.K., Berrih-Aknin, S., Bismuth, J., Bidault, J., Fuchs, S., Souroujon, M.C. J. Immunol. (2005) [Pubmed]
  40. Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough. Hartl, D., Griese, M., Nicolai, T., Zissel, G., Prell, C., Konstantopoulos, N., Gruber, R., Reinhardt, D., Schendel, D.J., Krauss-Etschmann, S. J. Allergy Clin. Immunol. (2005) [Pubmed]
  41. CXCR3 and CCR5 positive T-cell recruitment in acute human renal allograft rejection. Panzer, U., Reinking, R.R., Steinmetz, O.M., Zahner, G., Sudbeck, U., Fehr, S., Pfalzer, B., Schneider, A., Thaiss, F., Mack, M., Conrad, S., Huland, H., Helmchen, U., Stahl, R.A. Transplantation (2004) [Pubmed]
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