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首页> 外文期刊>Rheumatology >Mitochondrial dysfunction promotes and aggravates the inflammatory response in normal human synoviocytes
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Mitochondrial dysfunction promotes and aggravates the inflammatory response in normal human synoviocytes

机译：线粒体功能障碍促进并加重正常人滑膜细胞的炎症反应

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Objectives: In RA, synoviocytes cause increased oxidative stress, leading to mitochondrial alterations that may participate in the pathogenesis of RA. Here we investigated whether mitochondrial dysfunction induces inflammatory responses in cultured normal human synoviocytes, a hallmark of RA. Methods: Mitochondrial dysfunction was induced with the inhibitor oligomycin. The effects of mitochondrial dysfunction on cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and IL-8 expression; cellular and mitochondrial reactive oxygen species (ROS) production; nuclear factor-κB (NF-κB) activation and p65 translocation were studied. ROS scavengers (N-acetylcysteine and mitoTEMPO) and an NF-κB inhibitor (BAY-117085) were used to investigate the pathways involved. The natural anti-inflammatory antioxidant resveratrol was also tested. Results: Mitochondrial dysfunction per se significantly stimulated mitochondrial ROS production as well as low-grade expressions of COX-2, PGE2 and IL-8. Interestingly, mitochondrial dysfunction induced by pretreatment of synoviocytes with oligomycin synergized with IL-1β to increase the expression of these inflammatory mediators. The inflammatory effects of mitochondrial damage appeared to be dependent on ROS production and NF-κB activation since the inflammatory response was counteracted by both N-acetylcysteine and mitoTEMPO and it was also reduced by BAY-117085. Antimycin A and paraquat (inhibitors of mitochondrial function) also induced inflammatory responses. Furthermore, resveratrol significantly reduced the inflammatory response by decreasing ROS production and NF-κB activation. Conclusion: These data suggest that mitochondrial dysfunction could induce an inflammatory response in normal human synoviocytes and sensitize these cells, causing a significant amplification of the inflammatory response induced by IL-1β. Resveratrol may represent a promising strategy in controlling the synovial inflammatory response.
机译：目的：在RA中，滑膜细胞导致氧化应激增加，导致线粒体改变，可能参与RA的发病机理。在这里，我们调查了线粒体功能障碍是否在培养的正常人滑膜细胞（RA的标志）中诱发炎症反应。方法：用抑制剂寡霉素诱导线粒体功能障碍。线粒体功能障碍对环氧合酶2（COX-2），前列腺素E2（PGE2）和IL-8表达的影响;细胞和线粒体活性氧（ROS）的产生;研究了核因子-κB（NF-κB）激活和p65易位。使用ROS清除剂（N-乙酰半胱氨酸和mitoTEMPO）和NF-κB抑制剂（BAY-117085）来研究所涉及的途径。还测试了天然抗炎抗氧化剂白藜芦醇。结果：线粒体功能障碍本身可明显刺激线粒体ROS的产生以及COX-2，PGE2和IL-8的低度表达。有趣的是，通过用与IL-1β协同作用的寡霉素预处理滑膜细胞诱导的线粒体功能障碍，从而增加了这些炎症介质的表达。线粒体损伤的炎性作用似乎取决于ROS的产生和NF-κB的激活，因为N-乙酰半胱氨酸和mitoTEMPO都抵消了炎症反应，而BAY-117085也降低了炎症反应。抗霉素A和百草枯（线粒体功能抑制剂）也可引起炎症反应。此外，白藜芦醇可通过减少ROS的产生和NF-κB的活化来显着降低炎症反应。结论：这些数据表明线粒体功能障碍可在正常人滑膜细胞中引起炎症反应并使这些细胞增敏，从而导致IL-1β诱导的炎症反应显着放大。白藜芦醇可能代表控制滑膜炎性反应的有前途的策略。

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