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Chemokine-mediated inflammation: Identification of a possible regulatory role for CCR2

Lookup NU author(s): Dr Graeme O'Boyle, Dr John Brain, Professor John Kirby, Professor Simi Ali

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Abstract

The chemokine receptor CCR2 binds four pro-inflammatory monocyte chemoattractant proteins, designated MCP1/CCL2, MCP2/CCL8, MCP3/CCL7 and MCP4/CCL13. This study demonstrates the important biology of this receptor during the response to the chemokine milieu. Competitive chemotaxis and calcium flux assays were performed utilising mixtures of chemokines to assess a hierarchal arrangement of chemokine prepotency; these demonstrated that the MCP2-CCR2 interaction is able to supersede signals generated by RANTES, another pro-inflammatory chemokine, or the homeostatic chemokine SDF1. These observations were validated using three physiologically relevant monocytic cell lines. Having identified the importance of CCR2, experiments were then performed to examine the signal transduction processes coupled to this receptor. G protein coupling was initially examined; Cholera toxin reduced the chemotactic response to MCP2 (p < 0.001), whilst the response to the other MCP chemokines remained normal. The response to MCP2 was uniquely inhibited by elevated concentrations of cAMP and, unlike MCP1, 3 and 4 (p < 0.05), MCP2 failed to inhibit adenylate cyclase. Expression of dominant negative H-ras demonstrated that each MCP chemokine required active ras in order to elicit ERK activation and a chemotactic response. Unlike MCP1, MCP2 failed to induce nuclear translocation of activated ERK1 or subsequent induction of c-Myc expression. Akt activation also showed ligand-specific differences, with MCP2 producing a delayed response compared to the other MCP chemokines. Together these data highlight the importance of CCR2 and suggest that it is a powerful tool for fine tuning the immune response. © 2006 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): O'Boyle G, Brain JG, Kirby JA, Ali S

Publication type: Article

Publication status: Published

Journal: Molecular Immunology

Year: 2007

Volume: 44

Issue: 8

Pages: 1954-1963

Print publication date: 01/03/2007

ISSN (print): 0161-5890

ISSN (electronic): 1872-9142

Publisher: Pergamon

URL: http://dx.doi.org/10.1016/j.molimm.2006.09.026

DOI: 10.1016/j.molimm.2006.09.026


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