The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3.
Th1 and Th2 lymphocytes express a different repertoire of chemokine receptors (CCRs). CXCR3, the receptor for I-TAC (interferon-inducible T cell alpha-chemoattractant), Mig (monokine induced by gamma-interferon), and IP10 (interferon-inducible protein 10), is expressed preferentially on Th1 cells, whereas CCR3, the receptor for eotaxin and several other CC chemokines, is characteristic of Th2 cells. While studying responses that are mediated by these two receptors, we found that the agonists for CXCR3 act as antagonists for CCR3. I-TAC, Mig, and IP10 compete for the binding of eotaxin to CCR3-bearing cells and inhibit migration and Ca(2+) changes induced in such cells by stimulation with eotaxin, eotaxin-2, MCP-2 (monocyte chemottractant protein-2), MCP-3, MCP-4, and RANTES (regulated on activation normal T cell expressed and secreted). A hybrid chemokine generated by substituting the first eight NH(2)-terminal residues of eotaxin with those of I-TAC bound CCR3 with higher affinity than eotaxin or I-TAC (3- and 10-fold, respectively). The hybrid was 5-fold more potent than I-TAC as an inhibitor of eotaxin activity and was effective at concentrations as low as 5 nm. None of the antagonists described induced the internalization of CCR3, indicating that they lack agonistic effects and thus qualify as pure antagonists. 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.
Loetscher
P
P
Theodor-Kocher Institute, University of Bern, P. O. Box 99, CH-3000 Bern 9, Switzerland. pius.loetscher@tki.unibe.ch
Pellegrino
A
A
Gong
J H
JH
Mattioli
I
I
Loetscher
M
M
Bardi
G
G
Baggiolini
M
M
Clark-Lewis
I
I
D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000737:chemistry / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology; D054397:Receptors, CCR3; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
C515456:CCL11 protein, human; C099677:CCL13 protein, human; C515350:CCR3 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054413:Chemokine CCL11; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D018945:Monocyte Chemoattractant Proteins; D054397:Receptors, CCR3; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D002118:Calcium