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Journal of Lipid Research, Vol. 49, 2323-2337, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Specific and overlapping sphingosine-1-phosphate receptor functions in human synoviocytes: impact of TNF-

Chenqi Zhao^*, Maria J. Fernandes^*, Mélanie Turgeon^*, Sabrina Tancrède^*, John Di Battista, Patrice E. Poubelle^* and Sylvain G. Bourgoin^1,*

^* Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ-CHUL, Départements d'Anatomie-Physiologie et Médecine, Faculté de Médecine, Université Laval, Québec, Canada, G1V 4G2
Département de Rhumatologie et Immunologie, Centre Universitaire McGill, Montréal, Québec, Canada, H3A 1A1

Published, JLR Papers in Press, July 24, 2008.

This project is supported by research grants from Canadian Institutes of Health Research and the Arthritis Society of Canada (S.G.B.) and the Canadian Arthritis Network Post-Doctoral Fellowship Award (C.Z.).

¹ To whom correspondence should be addressed. e-mail: sylvain.bourgoin{at}crchul.ulaval.ca

Sphingosine-1-phosphate (S1P), via interaction with its G protein-coupled receptors, regulates various physiological and pathological responses. The present study investigated the role of S1P/S1P receptor signaling in several functional responses of human fibroblast-like synoviocytes (FLSs) that may contribute to the pathogenesis of rheumatoid arthritis (RA). We report that FLSs express the S1P₁, S1P₂, and S1P₃ receptors. Moreover, exogenously applied S1P induces FLS 1) migration, 2) secretion of inflammatory cytokines/chemokines, and 3) protection from apoptosis. Using specific S1P receptor agonists/antagonists, we determined that S1P stimulates FLS migration through S1P₁ and S1P₃, induces cytokine/chemokine secretion through S1P₂ and S1P₃, and protects from cell apoptosis via S1P₁. The S1P-mediated cell motility and cytokine/chemokine secretion seem to be regulated by the p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, and Rho kinase signal transduction pathways. Interestingly, treatment of FLSs with tumor necrosis factor- increases S1P₃ expression and correlates with the enhancement of S1P-induced cytokine/chemokine production. Our data suggest that S1P₁, S1P₂, and S1P₃ play essential roles in the pathogenesis of RA by modulating FLS migration, cytokine/chemokine production, and cell survival. Moreover, the cytokine-rich environment of the inflamed synovium may synergize with S1P signaling to exacerbate the clinical manifestations of this autoimmune disease.

Supplementary key words inflammation • G protein-coupled receptor • interleukin-8 • cell migration • apoptosis • mitogen-activated protein kinase • Rho kinase

Abbreviations: COX-2, cyclooxygenase-2; EDG, endothelial differentiation gene; FLS, fibroblast-like synoviocyte; GM-CSF, granulocyte-monocyte colony-stimulating factor; IL, interleukin; IP-10, interferon--inducible protein 10; LPA, lysophosphatidic acid; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein-1; MIP-1, macrophage inflammatory protein-1; PGE₂, prostaglandin E₂; RA, rheumatoid arthritis; RANTES, regulated on activation normal T cells expressed and secreted; S1P, sphingosine-1-phosphate; SNP, sodium nitroprusside; TNF-, tumor necrosis factor-

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