Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.
Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.
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DOI：
10.1002/art.39086
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发表时间：
2015-06
影响因子：
13.3
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
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作者：
Yoshida, Yuji;Ogata, Atsushi;Kang, Sujin;Ebina, Kousuke;Shi, Kenrin;Nojima, Satoshi;Kimura, Tetsuya;Ito, Daisuke;Morimoto, Keiko;Nishide, Masayuki;Hosokawa, Takashi;Hirano, Toru;Shima, Yoshihito;Narazaki, Masashi;Tsuboi, Hideki;Saeki, Yukihiko;Tomita, Tetsuya;Tanaka, Toshio;Kumanogoh, Atsushi
Semaphorin 4D（Sema 4D）/CD 100在免疫激活、血管生成、骨代谢和神经发育中具有多效性作用。我们进行了这项研究，调查Sema 4D在类风湿关节炎（RA）中的作用。通过酶联免疫吸附试验分析血清和滑液中的可溶性Sema 4D（sSema 4D）水平。分析RA患者外周血细胞中Sema 4D的细胞表面表达和转录，并在RA滑膜中进行Sema 4D的免疫组织化学染色。在ADAMTS-4处理的单核细胞系（THP-1细胞）中评价sSema 4D的产生。在患有胶原诱导的关节炎（CIA）的小鼠中评价抗Sema 4D抗体的功效。RA患者血清和滑液中sSema 4D水平升高，疾病活动标志物与血清sSema 4D水平相关。Sema 4D表达细胞也聚集在RA滑膜中。RA患者CD 3+和CD 14+细胞表面Sema 4D水平降低，但Sema 4D转录水平不变。此外，ADAMTS-4切割细胞表面Sema 4D以在THP-1细胞中产生sSema 4D。可溶性Sema 4D诱导CD 14+单核细胞产生肿瘤坏死因子α（TNFα）和白细胞介素-6（IL-6）。IL-6和TNFα诱导滑膜细胞中ADAMTS-4的表达。用抗Sema 4D抗体治疗可抑制关节炎并减少CIA中促炎细胞因子的产生。sSema 4D/IL-6和TNFα/ADAMTS-4的正反馈回路可能参与RA的发病机制。抗Sema 4D抗体对关节炎的抑制表明Sema 4D代表了RA的潜在治疗靶点。
Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme‐linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS‐4–treated monocytic cell line (THP‐1 cells). The efficacy of anti‐Sema4D antibody was evaluated in mice with collagen‐induced arthritis (CIA). Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D‐expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS‐4 cleaved cell surface Sema4D to generate sSema4D in THP‐1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) production from CD14+ monocytes. IL‐6 and TNFα induced ADAMTS‐4 expression in synovial cells. Treatment with an anti‐Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. A positive feedback loop involving sSema4D/IL‐6 and TNFα/ADAMTS‐4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti‐Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.
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影响因子：
3.7
作者：
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通讯作者：
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影响因子：
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