Mitochondrial dysfunction promotes and aggravates the inflammatory response in normal human synoviocytes

作者：Valcarcel Ares Marta N; Riveiro Naveira Romina R; Vaamonde Garcia Carlos; Loureiro Jesus^*; Hermida Carballo Laura; Blanco Francisco J; Lopez Armada Maria J

来源：Rheumatology, 2014, 53(7): 1332-1343.

DOI：10.1093/rheumatology/keu016

• mitochondria
• oxidative stress
• inflammation
• synoviocytes
• rheumatoid arthritis
• resveratrol

Methods. Mitochondrial dysfunction was induced with the inhibitor oligomycin. The effects of mitochondrial dysfunction on cyclooxygenase-2 (COX-2), prostaglandin E-2 (PGE(2)) and IL-8 expression; cellular and mitochondrial reactive oxygen species (ROS) production; nuclear factor-kappa B (NF-kappa B) activation and p65 translocation were studied. ROS scavengers (N-acetylcysteine and mitoTEMPO) and an NF-kappa B 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, PGE(2) and IL-8. Interestingly, mitochondrial dysfunction induced by pretreatment of synoviocytes with oligomycin synergized with IL-1 beta to increase the expression of these inflammatory mediators. The inflammatory effects of mitochondrial damage appeared to be dependent on ROS production and NF-kappa B 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-kappa B 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-1 beta. Resveratrol may represent a promising strategy in controlling the synovial inflammatory response.