Abstract
BackgroundSphingosine-1-phosphate receptor 3 (S1P3) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P3 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 S1P3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs.MethodsWild-type (WT) and S1P3 knockout (S1P3-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). S1P3 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 S1P3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P3 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.ResultsClinical and histological scores, and synovial IL-6 expression were significantly lower in S1P3-KO mice with CIA than in WT mice. Arthritic synovia had higher S1P3 expression than intact synovia and FLSs in arthritic joints expressed S1P3 in vivo. Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P3 expression after activation with TNFα. S1P3-induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα.ConclusionIn this study, we demonstrated that S1P3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P3 signaling could open the door to the development of new therapies for RA.
Highlights
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that can cause cartilage damage, bone erosion, and joint dysfunction, resulting in irreversible disability [1]
Levels of S1P are higher in the synovial fluid of rheumatoid arthritis (RA) patients than in that of osteoarthritis (OA) patients [7], and the expression of Sphingosine-1-phosphate receptor 3 (S1P3) in fibroblast-like synoviocytes (FLSs) from RA patients is upregulated by tumor necrosis factor α (TNFα) in vitro [8]
We demonstrated that S1P3 expression contributes to the Upregulation of sphingosine-1-phosphate receptor 3 on synoviocytes in collagen-induced arthritis development of CIA via inflammation-induced upregulation of S1P/S1P3 signaling, which increases the production of IL-6 by FLSs
Summary
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that can cause cartilage damage, bone erosion, and joint dysfunction, resulting in irreversible disability [1]. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator involved in several physiological and pathological conditions including autoimmune disease, cardiovascular disease, cancer, sepsis, and bone metabolism [6]. Levels of S1P are higher in the synovial fluid of RA patients than in that of osteoarthritis (OA) patients [7], and the expression of S1P3 in fibroblast-like synoviocytes (FLSs) from RA patients is upregulated by TNFα in vitro [8]. These observations suggest that S1P/S1P3 signaling may be involved in the pathogenesis of RA. The aim of this study was to investigate whether S1P3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs
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