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 S1P(1), S1P(2), 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 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-alpha 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.
Highlights
Sphingosine-1-phosphate (S1P), via interaction with its G protein-coupled receptors, regulates various physiological and pathological responses
S1P1, S1P2, and S1P3 receptor expression in human fibroblast-like synoviocyte (FLS) Because the biological activity of S1P is via interaction with specific cell surface receptors, we examined whether human FLSs express all the known receptors for S1P
Oligonucleotide primers designed for S1P4 and S1P5 did not yield a detectable signal in human FLSs but amplified the expected 672 bp (S1P4) and 658 bp (S1P5) bands in human monocytes that were used as positive controls
Summary
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). 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. FLSs increase in number, invade adjacent tissues, and produce proinflammatory cytokines, chemokines, and matrix metalloproteinases that promote inflammation and joint destruction [2]. Proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b), appear to play a key role in the stimulation of FLSs toward this aggressive phenotype. S1P receptors activate a variety of heterologous signaling pathways through coupling with
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