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Originally published In Press as doi:10.1074/jbc.M103933200 on September 14, 2001

J. Biol. Chem., Vol. 276, Issue 46, 42957-42964, November 16, 2001
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The CC Chemokine Eotaxin (CCL11) Is a Partial Agonist of CC Chemokine Receptor 2b*

Roberta MartinelliDagger , Ian SabroeDagger , Greg LaRosa§, Timothy John WilliamsDagger , and James Edward PeaseDagger

From the Dagger  Leukocyte Biology Section, Biomedical Sciences Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College of Science, Technology, and Medicine, South Kensington, London SW7 2AZ, United Kingdom and § Millennium Pharmaceuticals Inc., Cambridge, Massachusetts 02139

Despite sharing considerable homology with the members of the monocyte chemoattractant protein (MCP) family, the CC chemokine eotaxin (CCL11) has previously been reported to signal exclusively via the receptor CC chemokine receptor 3 (CCR3). Using the monocyte cell line THP-1, we investigated the relative abilities of eotaxin and MCPs 1-4 to induce CCR2 signaling, employing assays of directed cell migration and intracellular calcium flux. Surprisingly, 1 µM concentrations of eotaxin were able to recruit THP-1 cells in chemotaxis assays, and this migration was sensitive to antagonism of CCR2 but not CCR3. Radiolabeled eotaxin binding assays performed on transfectants bearing CCR2b or CCR3 confirmed eotaxin binding to CCR2 with a Kd of 7.50 ± 3.30 nM, compared with a Kd of 1.68 ± 0.91 nM at CCR3. In addition, whereas 1 µM concentrations of eotaxin were able to recruit CCR2b transfectants, substimulatory concentrations of eotaxin inhibited MCP-1-induced chemotaxis of CCR2b transfectants and also inhibited MCP-1-induced intracellular calcium flux of THP-1 cells. Collectively, these findings suggest that eotaxin is a partial agonist of the CCR2b receptor. A greater understanding of the interaction of CCR2 with all of its ligands, both full and partial agonists, may aid the rational design of specific antagonists that hold great promise as future therapeutic treatments for a variety of inflammatory disorders.

* This work was supported by the Arthritis Research Campaign (Project PO556) (to R. M.), the Medical Research Council (to I. S.), the Wellcome Trust (Program Grant 038775/Z/96/A) (to J. E. P.), and the National Asthma Campaign (to T. J. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Leukocyte Biology Section, Biomedical Sciences Division, Faculty of Medicine, Sir Alexander Fleming Bldg., Imperial College of Science, Technology, and Medicine, South Kensington, London SW7 2AZ, UK. Tel.: 44 020 7594 3162; Fax: 44 020 7594 3119; E-mail: j.pease@ic.ac.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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