**4.4.4 Synergistic action of S1P and TNF- on synovial fibroblast functions**

TNF- is central to RA pathogenesis as the pro-inflammatory cytokine not only stimulates the production of other inflammatory mediators but also directly triggers the activation of synovial cells and osteoclasts leading to the irreversible damage of soft tissues and bone (Olsen and Stein, 2004). Several studies have suggested that S1P and TNF- might synergize in their regulation of synovial fibroblast functions. On the one hand, the expression of S1P3 receptor was enhanced by TNF-, leading to amplified secretion of cytokines/chemokines, including IL-6, IL-8, MCP-1, and RANTES (Zhao et al., 2008). On the other hand, S1P enhanced TNF--mediated COX-2 expression and production of PGE2 by RA synoviocytes (Kitano et al., 2006). Thus, the elevated levels of TNF- seen in RA synovium may increase S1P synthesis via activation of SphKs and make synovial fibroblasts more responsive to S1P possibly through up-regulation of S1P receptor expression. The synergy between TNF- and S1P may eventually exacerbate the clinical manifestations of RA, including enhanced synovial tissue invasion by aggressive fibroblasts (due to enhanced cell mobility), synovial hyperplasia (due to proliferation and survival of synoviocytes), and exacerbated inflammation (due to over production of inflammatory mediators).
