Ferulic acid inhibits interleukin 17-dependent expression of nodal pathogenic mediators in fibroblast-like synoviocytes of rheumatoid arthritis
Ferulic acid inhibits interleukin 17-dependent expression of nodal pathogenic mediators in fibroblast-like synoviocytes of rheumatoid arthritis
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DOI：
10.1002/jcb.27502
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发表时间：
2019-02-01
影响因子：
4
通讯作者：
Rasool, Mahaboobkhan
中科院分区：
文献类型：
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作者：
Ganesan, Ramamoorthi;Rasool, Mahaboobkhan
白细胞介素17（IL - 17）是一种由辅助性T细胞（Th）17细胞产生的促炎细胞因子，可能通过IL - 17/白细胞介素17受体A型（IL - 17RA）/信号转导和转录激活因子3（STAT - 3）信号级联来控制类风湿关节炎（RA）中由成纤维样滑膜细胞（FLS）介导的疾病活动。这表明靶向IL - 17信号通路可作为治疗由FLS介导的RA进展的重要策略。阿魏酸（FA）是一种关键的多酚，通过其抗炎作用减轻痛风性关节炎和癌症的发展，但其在由FLS介导的RA发病机制中对IL - 17信号通路的治疗效果仍不清楚。在本研究中，FA显著抑制从佐剂诱导性关节炎（AA）大鼠分离的FLS中IL - 17介导的其特异性跨膜受体IL - 17RA的表达。重要的是，FA通过抑制IL - 17/IL - 17RA/STAT - 3信号级联，显著抑制AA - FLS中IL - 17介导的Toll样受体3（TLR - 3）、富含半胱氨酸的血管生成诱导因子61（Cyr61）、IL - 23、粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）的表达。此外，在由IL - 17处理的AA - FLS和大鼠骨髓来源的单核细胞/巨噬细胞组成的共培养系统中，FA显著降低破骨细胞的形成和骨吸收潜能。进一步地，FA通过调节IL - 17/IL - 17RA/STAT - 3信号级联，显著抑制AA - FLS中核因子 - κB受体激活剂配体（RANKL）的IL - 17介导的表达，并增加骨保护素（OPG）的表达。通过使用小干扰RNA敲低IL - 17RA或用S3I - 201阻断STAT - 3激活，进一步证实了FA对IL - 17信号通路的治疗效果。分子对接分析显示，FA对IL - 17RA、STAT - 3、IL - 23和RANKL蛋白表现出显著的配体效率。本研究提供了新的证据，表明FA可作为一种潜在的治疗药物，用于抑制RA中IL - 17介导的疾病严重程度和骨侵蚀。
Interleukin 17 (IL-17), a proinflammatory cytokine produced by T helper (Th) 17 cells, potentially controls fibroblast-like synoviocytes (FLS)-mediated disease activity of rheumatoid arthritis (RA) via IL-17/ IL-17 receptor type A (IL-17RA)/signal transducer and activator of transcription 3 (STAT-3) signaling cascade. This has suggested that targeting IL-17 signaling could serve as an important strategy to treat FLS-mediated RA progression. Ferulic acid (FA), a key polyphenol, attenuates the development of gouty arthritis and cancer through its anti-inflammatory effects, but its therapeutic efficiency on IL-17 signaling in FLS-mediated RA pathogenesis remains unknown. In the current study, FA markedly inhibited the IL-17-mediated expression of its specific transmembrane receptor IL-17RA in FLS isolated from adjuvant-induced arthritis (AA) rats. Importantly, FA dramatically suppressed the IL-17-mediated expression of toll-like receptor 3 (TLR-3), cysteine-rich angiogenic inducer 61 (Cyr61), IL-23, granulocyte-macrophage colony stimulating factor (GM-CSF) in AA-FLS via the inhibition of IL-17/IL-17RA/STAT-3 signaling cascade. In addition, FA significantly decreased the formation of osteoclast cells and bone resorption potential in a coculture system consisting of IL-17 treated AA-FLS and rat bone marrow derived monocytes/macrophages. Furthermore, FA remarkably inhibited the IL-17-mediated expression of receptor activator of nuclear factor -B ligand(RANKL) and increased the expression of osteoprotegerin(OPG) in AA-FLS via the regulation of IL-17/IL-17RA/STAT-3 signaling cascade. The therapeutic efficiency of FA on IL-17 signaling was further confirmed by knockdown of IL-17RA using small interfering RNA or blocking of STAT-3 activation with S3I-201. The molecular docking analysis revealed that FA manifests significant ligand efficiency toward IL-17RA, STAT-3, IL-23, and RANKL proteins. This study provides new evidence that FA can be used as a potential therapeutic agent for inhibiting IL-17-mediated disease severity and bone erosion in RA.