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J. Biol. Chem., Vol. 279, Issue 50, 52797-52805, December 10, 2004

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Signaling Events Involved in Macrophage Chemokine Expression in Response to Monosodium Urate Crystals^*

Maritza Jaramillo, Marianne Godbout¶||, Paul H. Naccache**, and Martin Olivier¶

From the ^¶Research Institute of the McGill University Health Centre, Centre for the Study of Host Resistance, Departments of Medicine, Microbiology, and Immunology, McGill University, Montréal, Québec H3A 2B4, Canada, Centre de Recherche en Infectiologie and ^**Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon Centre Hospitalier de l'Université Laval and Départements de Biologie Médicale et de Médecine, Faculté de Médecine, Université Laval, Ste-Foy, Québec G1V 4G2, Canada

Chemokine production has been associated with leukocyte infiltration into the joint during gouty arthritis, and monosodium urate (MSU) crystals, the causative agent of this arthropathy, have been shown to modulate their expression. In the present study, we investigated the transductional mechanisms underlying this cellular regulation in the murine macrophage cell line B10R. We report that MSU crystals rapidly and transiently increase mRNA levels of various chemokines in a concentration-dependent manner. Examination of second messenger activation revealed that macrophage exposure to MSU crystals led to MEK1/2, ERK1/2, and inhibitory protein B phosphorylation as well as to NF-B and AP-1 nuclear translocation. Of interest, specific blockage of the ERK1/2 pathway drastically reduced up-modulation of MSU crystal-mediated chemokine production and activation of nuclear factors. Similarly, selective inhibition of NF-B suppressed NF-B DNA binding activity and the induction of all chemokine transcripts. These findings indicate that ERK1/2-dependent signals seem to be required for AP-1 and NF-B activation and subsequent mRNA expression of the various macrophage chemokines. In addition, transcription and stability assays performed in presence of actinomycin D showed that MSU crystal-mediated MIP-1 mRNA up-regulation resulted solely from transcriptional control, whereas that of MIP-1, MIP-2, and MCP-1 was due to both gene transcription activation and mRNA posttranscriptional stabilization. Overall, the results of this study help to define the molecular events that govern macrophage chemokine regulation in response to MSU crystals, which is of paramount importance to better understand, and eventually to tame, the inflammatory response during acute gout.

Received for publication, April 6, 2004 , and in revised form, September 28, 2004.

^* This work was supported in part by grants from the Canadian Institutes in Health Research (CIHR) (to M. O.) and from the Arthritis Society (to P. H. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Ministère de l'Éducation du Québec Ph.D. studentship.

^|| Recipient of a Fonds pour la Formation de Chercheurs et l'Aide à la Recherche M.Sc. studentship.

Recipient of the Canada Research Chair on the Molecular Physiopathology of the Neutrophil.

Member of a CIHR group in host-pathogen interactions. Recipient of a CIHR Investigator Award and a Burroughs Wellcome Fund Awardee in Molecular Parasitology. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, McGill University, 3775 University St., Duff Medical Bldg. (Rm. 600), Montréal, Québec H3A 2B4, Canada. Tel.: 514-398-5592; Fax: 514-398-7052; E-mail: martin.olivier{at}staff.mcgill.ca.

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