雷公藤内酯醇通过抑制 lncRNA RP11-83J16.1 介导的 URI1 和 β-连环蛋白信号通路降低类风湿关节炎成纤维样滑膜细胞的增殖、侵袭、炎症反应，并在胶原诱导性关节炎大鼠中呈现出治疗效果。
Triptolide decreases rheumatoid arthritis fibroblast-like synoviocyte proliferation, invasion, inflammation and presents a therapeutic effect in collagen-induced arthritis rats via inactivating lncRNA RP11-83J16.1 mediated URI1 and β-catenin signaling.
机构信息
Department of Rheumatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Health Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
出版信息
Int Immunopharmacol. 2021 Oct;99:108010. doi: 10.1016/j.intimp.2021.108010. Epub 2021 Aug 3.
OBJECTIVE
Our previous study observed that long non-coding RNA (lncRNA) RP11-83J16.1 promoted rheumatoid arthritis (RA)-fibroblast-like synoviocyte (RA-FLS) proliferation, invasion and inflammation, which was downregulated by triptolide treatment. Therefore, the present study aimed to further investigate the mechanism and interaction between triptolide and lncRNA RP11-83J16.1 in RA treatment in vitro and in vivo.
METHODS
RA-FLS was isolated and treated by different concentration of triptolide and lncRNA RP11-83J16.1 overexpression plasmid. Furthermore, collagen-induced arthritis (CIA) rat model was constructed followed by triptolide and lncRNA RP11-83J16.1 overexpression plasmid treatment.
RESULTS
Triptolide inhibited RA-FLS viability and lncRNA RP11-83J16.1 expression in a dose-dependent manner. Afterward, triptolide treatment inhibited RA-FLS proliferation, invasion, levels of inflammatory markers (TNF-α, IL-1β, IL-6, MMP-3, and MMP-9), inactivated lncRNA RP11-83J16.1, URI1 and β-catenin signaling, but promoted apoptosis. However, lncRNA RP11-83J16.1 overexpression weakened the effects of triptolide on regulating RA-FLS cell behaviors, URI1 signaling and β-catenin signaling. In CIA model, triptolide decreased arthritis score, hyperproliferation of synovial cells, inflammation infiltration of synovial tissue, inflammatory markers (TNF-α, IL-1β, IL-6, MMP-3, and MMP-9), inactivated lncRNA RP11-83J16.1, URI1 and β-catenin signaling, but increased cell apoptosis rate of synovial tissue. Nevertheless, lncRNA RP11-83J16.1 curtailed the treatment effect of triptolide in CIA model.
CONCLUSION
Triptolide decreases RA-FLS proliferation, invasion, inflammation and presents a therapeutic effect in CIA model via inactivating lncRNA RP11-83J16.1 mediated URI1 and β-catenin signaling.
目的
我们之前的研究观察到长链非编码 RNA（lncRNA）RP11-83J16.1 促进类风湿关节炎（RA）成纤维样滑膜细胞（RA-FLS）增殖、侵袭和炎症，而雷公藤内酯醇治疗可下调其表达。因此，本研究旨在进一步探讨雷公藤内酯醇和 lncRNA RP11-83J16.1 在 RA 治疗中的体外和体内相互作用机制。
方法
分离并培养 RA-FLS，用不同浓度的雷公藤内酯醇和 lncRNA RP11-83J16.1 过表达质粒进行处理。此外，构建胶原诱导性关节炎（CIA）大鼠模型，并进行雷公藤内酯醇和 lncRNA RP11-83J16.1 过表达质粒治疗。
结果
雷公藤内酯醇呈剂量依赖性抑制 RA-FLS 活力和 lncRNA RP11-83J16.1 的表达。随后，雷公藤内酯醇治疗抑制 RA-FLS 增殖、侵袭、炎症标志物（TNF-α、IL-1β、IL-6、MMP-3 和 MMP-9）水平，激活 lncRNA RP11-83J16.1、URI1 和 β-catenin 信号，但促进细胞凋亡。然而，lncRNA RP11-83J16.1 过表达削弱了雷公藤内酯醇对 RA-FLS 细胞行为、URI1 信号和 β-catenin 信号的调节作用。在 CIA 模型中，雷公藤内酯醇降低关节炎评分、滑膜细胞过度增殖、滑膜组织炎症浸润、炎症标志物（TNF-α、IL-1β、IL-6、MMP-3 和 MMP-9）水平，激活 lncRNA RP11-83J16.1、URI1 和 β-catenin 信号，但增加滑膜组织细胞凋亡率。然而，lncRNA RP11-83J16.1 抑制了雷公藤内酯醇在 CIA 模型中的治疗作用。
结论
雷公藤内酯醇通过抑制 lncRNA RP11-83J16.1 介导的 URI1 和 β-catenin 信号，减少 RA-FLS 的增殖、侵袭、炎症，并在 CIA 模型中表现出治疗作用。
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