title: I-TAC/CXCL11 is a natural antagonist for CCR5.
abstract: The selective CXC chemokine receptor 3 (CXCR3) agonists, monokine induced by interferon-gamma (IFN- gamma)/CXC chemokine ligand 9 (CXCL9), IFN-inducible protein 10/CXCL10, and IFN-inducible T cell alpha chemoattractant (I-TAC)/CXCL11, attract CXCR3+ cells such as CD45RO+ T lymphocytes, B cells, and natural killer cells. Further, all three chemokines are potent, natural antagonists for chemokine receptor 3 (CCR3) and feature defensin-like, antimicrobial activities. In this study, we show that I-TAC, in addition to these effects, acts as an antagonist for CCR5. I-TAC inhibited the binding of macrophage-inflammatory protein-1alpha (MIP-1alpha)/CC chemokine ligand 3 (CCL3) to cells transfected with CCR5 and to monocytes. Furthermore, cell migration evoked by regulated on activation, normal T expressed and secreted (RANTES)/CCL5 and MIP-1beta/CCL4, the selective agonist of CCR5, was inhibited in transfected cells and monocytes, respectively. In two other functional assays, namely the release of free intracellular calcium and actin polymerization, I-TAC reduced CCR5 activities to minimal levels. Sequence and structure analyses indicate a potential role for K17, K49, and Q51 of I-TAC in CCR5 binding. Our results expand on the potential role of I-TAC as a negative modulator in leukocyte migration and activation, as I-TAC would specifically counteract the responses mediated by many "classical," inflammatory chemokines that act not only via CCR3 but via CCR5 as well.
authors.affiliation: Institute for Research in Biomedicine, Ballinzona, Switzerland.
authors.forename: Vibor
authors.initials: V
authors.lastname: Petkovic
authors.forename: Christian
authors.initials: C
authors.lastname: Moghini
authors.forename: Samantha
authors.initials: S
authors.lastname: Paoletti
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
authors.forename: Basil
authors.initials: B
authors.lastname: Gerber
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001483:Base Sequence / Q000502:physiology; D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000502:physiology; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000276:immunology* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000276:immunology; D017386:Sequence Homology, Amino Acid
chemical_list: D000199:Actins; C515350:CCR3 protein, human; D065100:CCR5 Receptor Antagonists; C515202:CXCL11 protein, human; C515351:Ccr3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; D019402:Macrophage Inflammatory Proteins; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine