Background Sphingosine-1-phosphate receptor 3 (S1P 3 ) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P 3 signaling is involved in numerous physiological and pathological processes including bone metabolism, sepsis, cancer, and immunity. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) are activated by several factors and promote abundant proinflammatory cytokine production and bone destruction. The aim of this study was to investigate whether S1P 3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs. Methods Wild-type (WT) and S1P 3 knockout (S1P 3 -KO) collagen-induced arthritis (CIA) mice were evaluated with respect to clinical and histological disease severity, along with the levels of anti-collagen antibodies and expression of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). S1P 3 expression in the synovium was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. FLSs isolated from CIA mice were activated with TNFα and S1P 3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P 3 signaling in activated and non-activated FLSs was investigated by measuring cell proliferation and cyto/chemokine production by real-time RT-PCR and/or enzyme-linked immunosorbent assay. Results Clinical and histological scores, and synovial IL-6 expression were significantly lower in S1P 3 -KO mice with CIA than in WT mice. Arthritic synovia had higher S1P 3 expression than intact synovia and FLSs in arthritic joints expressed S1P 3 in vivo . Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P 3 expression after activation with TNFα. S1P 3 -induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα. Conclusion In this study, we demonstrated that S1P 3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P 3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P 3 signaling could open the door to the development of new therapies for RA.

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