Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium - Regulation of synovial proliferation and inflammatory gene expression
Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium - Regulation of synovial proliferation and inflammatory gene expression
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DOI：
10.1002/art.21668
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发表时间：
2006-03-01
影响因子：
--
通讯作者：
Sano, H
中科院分区：
文献类型：
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作者：
Kitano, M;Hla, T;Sano, H
Objective. 1-磷酸鞘氨醇（S1 P）参与多种病理状态，并被认为是血管生成的重要介质。炎症、癌症和自身免疫。本研究旨在探讨S1 P/S1 P（1）信号在类风湿关节炎（RA）发病机制中的作用。我们检测了S1 P（1）信使RNA。（mRNA）和蛋白质水平。在RA滑膜细胞和MH 7A细胞中通过逆转录-聚合酶链反应和蛋白质印迹。我们还对28例RA患者和18例骨关节炎（OA）患者的滑膜组织进行了S1 P（1）免疫组织化学分析。我们采用WST-1法检测SIP对RA滑膜细胞增殖的影响，采用Western blotting和酶联免疫吸附法检测SIP对RA滑膜细胞和MH 7A细胞中肿瘤坏死因子α（TNF α）或白细胞介素1 β（IL-1 β）诱导的环氧合酶2（考克斯-2）表达和前列腺素E-2（PGE（2））产生的影响。最后，我们研究了SIP的这些作用是否对百日咳毒素（PTX）敏感，PTX是Gi/Go蛋白的抑制剂。RA滑膜细胞和MH 7A细胞中检测到SIP、mRNA和蛋白。与OA滑膜相比，S1 P（1）在RA滑膜衬里细胞、血管内皮细胞和炎性单核细胞中表达更强。S1 P可促进RA滑膜细胞和MH 7A细胞的增殖。S1 P单独作用可显著增强考克斯-2表达和PGE（2）生成。此外，S1 P可增强RA滑膜细胞和MH 7A细胞中由TNF α或IL-1 β刺激诱导的考克斯-2表达和PGE（2）产生。结论：紫杉醇预处理可抑制SIP的上述作用。这些结果表明，通过S1 P受体的S1 P信号传导在RA滑膜细胞的细胞增殖和炎症性奎宁诱导的考克斯-2表达和PGE（2）产生中起重要作用。因此，S1 P/S1 P（1）信号传导的调节可能。代表了RA的新治疗靶点。
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/S1P(1) signaling in the pathogenesis of rheumatoid arthritis (RA).Methods. We examined S1P(1) messenger RNA. (mRNA) and protein levels. in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P(1) immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of SIP on proliferation by WST-1 assay, and its effects on tumor necrosis factor alpha (TNF alpha)- or interleukin-1 beta (IL-1 beta)-induced cyclooxygenase 2 (COX-2) expression and prostaglandin E-2 (PGE(2)) production in RA synoviocytes and MH7A cells by Western blotting and enzyme-linked immunosorbent assay, respectively. Finally, we examined whether these effects of SIP were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins.Results. SIP, mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P(1) 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 PGE(2) production. Moreover, S1P enhanced expression of COX-2 and production of PGE(2) induced by stimulation with TNF alpha or IL-1 beta in RA synoviocytes and MH7A cells. These effects of SIP were inhibited by pretreatment with PTX.Conclusion. These findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine-induced COX-2 expression and PGE(2) production by RA synoviocytes. Thus, regulation of S1P/S1P(1) signaling may. represent a novel therapeutic target in RA.