Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
Mediators Inflamm. 2021 Dec 9;2021:6359652. doi: 10.1155/2021/6359652. eCollection 2021.
Ellagic acid (EA) was reported to play protective roles in rheumatoid arthritis (RA). It was found that the level of metastasis-associated gene 1 (MTA1)/histone deacetylase 1 (HDAC1) protein complex was downregulated by polyphenols in several human disorders. Notably, inhibition of MTA1 or HDAC1 has anti-inflammatory effects on RA. Therefore, our study is aimed at investigating whether EA prevents RA progression through regulating the MTA1/HDAC1 complex. Herein, the human fibroblast-like synoviocyte (FLS) cell line MH7A was treated with TNF- to induce an inflammation model in vitro and then incubated with different concentrations of EA. Western blot analysis showed that EA reduced MTA1 expression in a dose-dependent manner in MH7A cells. Then, TNF--treated MH7A cells were incubated with EA alone or together with MTA1 overexpression plasmid (pcDNA-MTA1), and we found that EA inhibited proliferation, inflammation cytokine levels, and oxidative stress marker protein levels and promoted apoptosis in MH7A cells, while MTA1 overexpression abolished these effects. Moreover, coimmunoprecipitation assay verified the interaction between MTA1 and HDAC1. EA downregulated the MTA1/HDAC1 complex in MH7A cells. MTA1 knockdown inhibited proliferation, inflammation, and oxidative stress and promoted apoptosis in MH7A cells, while HDAC1 overexpression reversed these effects. Moreover, chromatin immunoprecipitation assay indicated that EA inhibited HDAC1-mediated Nur77 deacetylation. Rescue experiments demonstrated that Nur77 knockdown reversed the effects of EA on MH7A cell biological behaviors. Additionally, EA treatment attenuated arthritis index, paw swelling, synovial hyperplasia, and inflammation in collagen-induced arthritis (CIA) rats. In conclusion, EA inhibited proliferation, inflammation, and oxidative stress and promoted apoptosis in MH7A cells and alleviated the severity of RA in CIA rats though downregulating MTA1/HDAC1 complex and promoting HDAC1 deacetylation-mediated Nur77 expression.
鞣花酸 (EA) 被报道在类风湿性关节炎 (RA) 中发挥保护作用。研究发现，多酚可下调几种人类疾病中转移相关基因 1 (MTA1)/组蛋白去乙酰化酶 1 (HDAC1) 蛋白复合物的水平。值得注意的是，抑制 MTA1 或 HDAC1 对 RA 具有抗炎作用。因此，我们的研究旨在探讨 EA 是否通过调节 MTA1/HDAC1 复合物来预防 RA 进展。在此，使用 TNF-处理人成纤维样滑膜细胞 (FLS) 细胞系 MH7A 以在体外诱导炎症模型，然后用不同浓度的 EA 孵育。Western blot 分析显示，EA 以剂量依赖性方式降低 MH7A 细胞中的 MTA1 表达。然后，将 TNF--处理的 MH7A 细胞与 EA 单独或与 MTA1 过表达质粒 (pcDNA-MTA1) 一起孵育，我们发现 EA 抑制 MH7A 细胞的增殖、炎症细胞因子水平和氧化应激标志物蛋白水平，并促进 MH7A 细胞凋亡，而 MTA1 过表达则消除了这些作用。此外，共免疫沉淀测定验证了 MTA1 和 HDAC1 之间的相互作用。EA 下调 MH7A 细胞中的 MTA1/HDAC1 复合物。MTA1 敲低抑制 MH7A 细胞的增殖、炎症和氧化应激，并促进其凋亡，而 HDAC1 过表达则逆转了这些作用。此外，染色质免疫沉淀测定表明，EA 抑制了 HDAC1 介导的 Nur77 去乙酰化。挽救实验表明，Nur77 敲低逆转了 EA 对 MH7A 细胞生物学行为的影响。此外，EA 治疗可减轻胶原诱导性关节炎 (CIA) 大鼠的关节炎指数、足肿胀、滑膜增生和炎症。总之，EA 通过下调 MTA1/HDAC1 复合物并促进 HDAC1 去乙酰化介导的 Nur77 表达，抑制 MH7A 细胞的增殖、炎症和氧化应激并促进其凋亡，并减轻 CIA 大鼠 RA 的严重程度。
