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 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-α 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.

Keywords

• inflammation
• G protein-coupled receptor
• interleukin-8
• cell migration
• apoptosis
• mitogen-activated protein kinase