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

Chenqi Zhao, Maria J. Fernandes, Mélanie Turgeon, Sabrina Tancrède, John Di Battista, Patrice E. Poubelle, Sylvain G. Bourgoin
2008 Journal of Lipid Research  
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 S1P 1 , S1P 2 , and S1P 3 receptors. Moreover, exogenously applied S1P induces FLS 1) migration, 2)
more » ... 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 S1P 1 and S1P 3 , induces cytokine/chemokine secretion through S1P 2 and S1P 3 , and protects from cell apoptosis via S1P 1 . 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 S1P 3 expression and correlates with the enhancement of S1P-induced cytokine/ chemokine production. Our data suggest that S1P 1 , S1P 2 , and S1P 3 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.-Zhao, C., M. J. Fernandes, M. Turgeon, S. Tancrède, J. Di Battista, P. E. Poubelle, and S. G. Bourgoin. Specific and overlapping sphingosine-1-phosphate receptor functions in human synoviocytes: impact of TNF-a. J. Lipid Res. 2008Res. . 49: 2323Res. -2337
doi:10.1194/jlr.m800143-jlr200 pmid:18658144 fatcat:ao25jvy73fgpvpgacnvm2m7tdm