4.7 Article

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

期刊

RHEUMATOLOGY
卷 53, 期 7, 页码 1332-1343

出版社

OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keu016

关键词

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

资金

  1. Fondo Investigacion Sanitaria, Spain [06/1670, 06CP/00292, 09/02340, PI12/02771, RD12/0009/0018]
  2. Secretaria Xeral I+D+I [PXIB916357PR, PS09/56, INCITE 07PXI916207ES, INCITE 08E1R916069ES, INCITE 09E1R916139ES, IN845B2010/176, 10CSA916035PR]

向作者/读者索取更多资源

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.

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