title: Mitochondrial dysfunction promotes and aggravates the inflammatory response in normal human synoviocytes.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Marta N
authors.initials: MN
authors.lastname: Valcárcel-Ares
authors.affiliation: 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.
authors.forename: Romina R
authors.initials: RR
authors.lastname: Riveiro-Naveira
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vaamonde-García
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Loureiro
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Hermida-Carballo
authors.affiliation: 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.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.affiliation: 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. Maria.Jose.Lopez.Armada@sergas.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: López-Armada
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D009840:Oligomycins; D017382:Reactive Oxygen Species; D013267:Stilbenes; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D000077185:Resveratrol
keywords: inflammation; mitochondria; oxidative stress; resveratrol; rheumatoid arthritis; synoviocytes