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

Abstract

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 S1P 3 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-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. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.