I-TAC/CXCL11 is a natural antagonist for CCR5

J Leukoc Biol. 2004 Sep;76(3):701-8. doi: 10.1189/jlb.1103570. Epub 2004 Jun 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Amino Acid Sequence / physiology
  • Animals
  • Base Sequence / physiology
  • Binding Sites / drug effects
  • Binding Sites / immunology
  • CCR5 Receptor Antagonists*
  • Calcium Signaling / drug effects
  • Calcium Signaling / immunology
  • Cell Line
  • Cells, Cultured
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL5 / immunology
  • Chemokine CCL5 / metabolism
  • Chemokine CXCL11
  • Chemokines, CXC / immunology*
  • Chemokines, CXC / metabolism
  • Chemokines, CXC / pharmacology
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / immunology*
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology*
  • Macrophage Inflammatory Proteins / immunology
  • Macrophage Inflammatory Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Protein Binding / drug effects
  • Protein Binding / immunology
  • Protein Structure, Tertiary / physiology
  • Receptors, CCR3
  • Receptors, CCR5 / immunology*
  • Receptors, CCR5 / metabolism
  • Receptors, Chemokine / immunology
  • Sequence Homology, Amino Acid

Substances

  • Actins
  • CCR3 protein, human
  • CCR5 Receptor Antagonists
  • CXCL11 protein, human
  • Ccr3 protein, mouse
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL5
  • Chemokine CXCL11
  • Chemokines, CXC
  • Cxcl11 protein, mouse
  • Macrophage Inflammatory Proteins
  • Receptors, CCR3
  • Receptors, CCR5
  • Receptors, Chemokine