Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis.
Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis.
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紫杉醇抑制类风湿关节炎滑膜细胞迁移和炎症介质产生
DOI：
10.3389/fphar.2021.714566
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发表时间：
2021
影响因子：
5.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Chen X;Lin H;Chen J;Wu L;Zhu J;Ye Y;Chen S;Du H;Li J
活化的成纤维细胞样滑膜细胞(Fls)在类风湿关节炎(RA)的发生发展中起着重要作用。开发能有效抑制RA-FLS异常激活的新药迫在眉睫。本研究使用RA-FLS细胞系MH7A和胶原性关节炎(CIA)小鼠来评价紫杉醇(PTX)的作用。结果表明，PTX以剂量依赖的方式抑制RA-FLS的迁移，并显著降低IL-6、IL-8和RANKL基因的自发表达以及肿瘤坏死因子-α诱导的IL-1β、IL-8、MMP8和MMP9基因的转录。但PTX对RA-FLS的细胞凋亡无明显影响。机制研究表明，PTX能显著抑制肿瘤坏死因子α诱导的丝裂原活化蛋白激酶途径中ERK1/2和JNK的磷酸化，并抑制肿瘤坏死因子α诱导的AKT、p70S6K、4EBP1和HIF-1α的激活。此外，PTX还能减轻CIA小鼠的滑膜炎和骨质破坏。结论：PTX通过靶向MAPK和AKT/mTOR信号通路抑制RA-FLS的迁移和炎症介质的产生，为其在RA治疗中的潜在应用提供了实验基础。
Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1 β, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.
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影响因子：
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影响因子：
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