Aging and Inflammation Research Lab and Osteoarticular and Aging Research Lab, Rheumatology Division, Institute of Biomedical Research (INIBIC), Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
Rheumatology (Oxford). 2014 Jul;53(7):1332-43. doi: 10.1093/rheumatology/keu016. Epub 2014 Mar 7.
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.
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.
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.
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.
在类风湿关节炎（RA）中，滑膜细胞导致氧化应激增加，导致线粒体改变，这可能参与 RA 的发病机制。在这里，我们研究了线粒体功能障碍是否会在培养的正常人滑膜细胞中引起炎症反应，这是 RA 的一个标志。
用抑制剂寡霉素诱导线粒体功能障碍。研究了线粒体功能障碍对环氧化酶-2（COX-2）、前列腺素 E2（PGE2）和白细胞介素-8（IL-8）表达、细胞和线粒体活性氧（ROS）产生、核因子-κB（NF-κB）激活和 p65易位的影响。使用 ROS 清除剂（N-乙酰半胱氨酸和 mitoTEMPO）和 NF-κB 抑制剂（BAY-117085）来研究涉及的途径。还测试了天然抗炎抗氧化剂白藜芦醇。
线粒体功能障碍本身就显著刺激了线粒体 ROS 的产生以及 COX-2、PGE2 和 IL-8 的低水平表达。有趣的是，用寡霉素预处理滑膜细胞诱导的线粒体功能障碍与 IL-1β协同作用，增加了这些炎症介质的表达。线粒体损伤的炎症作用似乎依赖于 ROS 产生和 NF-κB 激活，因为 N-乙酰半胱氨酸和 mitoTEMPO 都能抑制炎症反应，BAY-117085 也能减轻炎症反应。抗霉素 A 和百草枯（线粒体功能抑制剂）也诱导了炎症反应。此外，白藜芦醇通过减少 ROS 产生和 NF-κB 激活，显著降低了炎症反应。
这些数据表明，线粒体功能障碍可能在正常人滑膜细胞中引起炎症反应，并使这些细胞敏感，导致 IL-1β 诱导的炎症反应显著放大。白藜芦醇可能是控制滑膜炎症反应的一种有前途的策略。
