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Chemokine-mediated inflammation: Identification of a possible regulatory role for CCR2.
O'Boyle, Graeme; Brain, John G; Kirby, John A; Ali, Simi.
Afiliação
  • O'Boyle G; Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, University of Newcastle, Newcastle NE2 4HH, UK.
Mol Immunol ; 44(8): 1944-53, 2007 Mar.
Article em En | MEDLINE | ID: mdl-17081610
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.
Assuntos
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Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Quimiotaxia / Regulação da Expressão Gênica / Proteínas Quimioatraentes de Monócitos / Receptores de Quimiocinas Idioma: En Ano de publicação: 2007 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Quimiotaxia / Regulação da Expressão Gênica / Proteínas Quimioatraentes de Monócitos / Receptores de Quimiocinas Idioma: En Ano de publicação: 2007 Tipo de documento: Article