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Papers In Press, published online ahead of print July 24, 2008
J. Lipid Res., doi:10.1194/jlr.M800143-JLR200
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Anatomie et Physiologie, Université Laval, Québec, Québec G1V 4G2
Corresponding Author: 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 (FLS) that may contribute to the pathogenesis of rheumatoid arthritis (RA). We report that FLS express the S1P1, S1P2 and S1P3 receptors. Moreover, exogenously applied S1P induces FLS 1) migration, 2) secretion of inflammatory cytokine/chemokine, 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, whereas 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 FLS with TNF-a 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.
Revised on July 18, 2008
Accepted on July 23, 2008
Specific and overlapping sphingosine-1-phosphate receptor functions in human synoviocytes: impact of TNF-alpha
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