Sphingosine 1‐phosphate/sphingosine 1‐phosphate receptor 1 signaling in rheumatoid synovium: Regulation of synovial proliferation and inflammatory gene expression

作者：Masayasu Kitano, Timothy Hla, Masahiro Sekiguchi, Yutaka Kawahito, Rikio Yoshimura, Keiji Miyazawa, Tsuyoshi Iwasaki, Hajime Sano · 发表于：Arthritis & Rheumatism · 年份：2006 · DOI：10.1002/art.21668 · 被引用次数：165 · 研究领域：Sphingolipid Metabolism and Signaling、Rheumatoid Arthritis Research and Therapies、Spondyloarthritis Studies and Treatments

OBJECTIVE: Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA). METHODS: We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor alpha (TNFalpha)- or interleukin-1beta (IL-1beta)-induced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme-linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins. RESULTS: S1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX-2 expression and PGE2 production. Moreover, S1P enhanced express...