Piceatannol suppresses inflammation and promotes apoptosis in rheumatoid arthritis-fibroblast-like synoviocytes by inhibiting the NF-κB and MAPK signaling pathways
Piceatannol suppresses inflammation and promotes apoptosis in rheumatoid arthritis-fibroblast-like synoviocytes by inhibiting the NF-κB and MAPK signaling pathways
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DOI：
10.3892/mmr.2022.12696
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发表时间：
2022-05-01
影响因子：
3.4
通讯作者：
Ma, Jianfeng
中科院分区：
文献类型：
--
作者：
Gao, Xuezhong;Kang, Xiaodiao;Ma, Jianfeng
类风湿性关节炎（RA）是一种以滑膜为主要靶点的慢性炎症性疾病，可导致关节僵硬、畸形和功能障碍。迄今为止，没有有效的抗炎治疗可用于RA。白藜芦醇（PIC）是白藜芦醇的天然衍生物，据报道，它可以减轻炎症反应。为了评价PIC对RA的作用并确定PIC的潜在分子靶点，本研究进行了体外和体内实验。建立CIA大鼠模型，评价PIC的治疗作用。通过ELISA测量血液中的TNF-α、IL-1 β和IL-6水平。采用Western blotting、免疫荧光分析和逆转录-定量PCR（RT-qPCR）分析蛋白和mRNA的表达水平。在体外，RA成纤维细胞样滑膜细胞（FLS）用PIC预处理，随后用TNF-α刺激。结果显示，PIC显著上调促凋亡蛋白如Bax和切割的caspase-3的表达水平。PIC还显著减少促炎细胞因子的产生，包括PGE 2、IL-6和IL-1 β，并在mRNA和蛋白表达水平上显著下调环氧合酶-2的表达。此外，PIC下调MMP-3和MMP-13的表达，已发现它们在RA患者的滑膜中高度表达。从机制上讲，PIC能够显著下调参与NF-κ B和MAPK信号通路的蛋白质的表达水平。使用大鼠胶原诱导的关节炎模型的体内实验的结果表明，PIC降低关节炎评分，并在软骨中发挥有益作用，并显著降低MMP-13的表达。结论：PIC能抑制RA FLS的炎症反应，促进细胞凋亡，并对NF-κ B B和MAPK信号通路有明显的调节作用。因此，PIC可能是未来治疗RA的潜在药物。
Rheumatoid arthritis (RA) is a chronic inflammatory disease that mainly targets the synovial membrane, thus causing stiffness, deformity and dysfunction of joints. To date, no effective anti-inflammatory treatments are available for RA. Piceatannol (PIC) is a natural derivative of resveratrol, which has been reported to attenuate the inflammatory response. To evaluate the effect of PIC on RA and to determine the underlying molecular target of PIC, both in vitro and in vivo experiments were performed in the present study. A CIA rat model was established to evaluate the therapeutic effects of PIC. TNF-alpha, IL-1 beta and IL-6 levels in blood were measured by ELISA. Western blotting, immunofluorescence analysis and reverse transcription-quantitative PCR (RT-qPCR) were used to analyze the expression levels of protein and mRNA. In vitro, RA-fibroblast-like synoviocytes (FLSs) were pretreated with PIC and subsequently stimulated with TNF-alpha. The results revealed that PIC significantly upregulated the expression levels of proapoptotic proteins such as Bax and cleaved caspase-3. PIC also significantly reduced the production of proinflammatory cytokines, including PGE2, IL-6 and IL-1 beta, and significantly downregulated the expression of cyclooxygenase-2 at both the mRNA and protein expression levels. Furthermore, PIC downregulated the expression of MMP-3 and MMP-13, which have been found to be highly expressed in the synovium of patients with RA. Mechanistically, PIC was capable of significantly downregulating the expression levels of proteins involved in the NF-kappa B and MAPK signaling pathways. The results of the in vivo experiments using a rat collagen-induced arthritis model demonstrated that PIC decreased the arthritis score and exerted beneficial effects in cartilage and significantly reduced the expression of MMP-13. In conclusion, the findings of the present study revealed that PIC could suppress the inflammatory response, promote apoptosis, and exert a significant regulatory effect on the NF-kappa B and MAPK signaling pathways in RA-FLSs. Therefore, PIC may represent a potential drug for the future treatment of RA.