title: Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice.
abstract: OBJECTIVE
  To elucidate the role of reactive oxygen species (ROS) in arthritis and to identify targets of arthritis treatment in conditions with different levels of oxidant stress.
  
  
  RESULTS
  Through establishing an arthritis model by injecting arthritogenic serum into wild-type and NADPH oxidase 2 (NOX2)-deficient mice, we found that arthritis had a neutrophilic infiltrate and was more severe in Ncf1(-/-) mice, a mouse strain lacking the expression of the NCF1/p47(phox) component of NOX2. The levels of interleukin-1β (IL-1β) and IL-6 in inflamed joints were higher in Ncf1(-/-) than in controls. Antagonists of tumor necrosis factor-α (TNFα) and IL-1β were equally effective in suppressing arthritis in wild-type mice, while IL-1β blockade was more effective than TNFα blockade in Ncf1(-/-) mice. A treatment of caspase inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a cathepsin inhibitor alone, suppressed arthritic severity in the wild-type mice, while a treatment of cathepsin inhibitor and the combination treatment of a caspase inhibitor and a cathepsin inhibitor, but not a caspase inhibitor alone, were effective in treating Ncf1(-/-) mice. Consistently, cathepsin B was found to proteolytically process pro-IL-1β to its active form and this activity was suppressed by ROS.
  
  
  METHODS
  This novel mechanism of a redox-mediated immune regulation of arthritis through leukocyte-produced ROS is important for devising an optimal treatment for patients with different levels of tissue ROS.
  
  
  CONCLUSIONS
  Our results suggest that ROS act as a negative feedback to constrain IL-1β-mediated inflammation, accounting for the more severe arthritis in the absence of NOX2.
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .
authors: Ya-Fang
authors: YF
authors: Huang
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .
authors: Pei-Chi
authors: PC
authors: Lo
authors: 2 Institute of Basic Medical Science, National Cheng Kung University College of Medicine , Tainan, Taiwan .
authors: Chia-Liang
authors: CL
authors: Yen
authors: 3 Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital , Boston, Massachusetts.|4 Division of Immunology, Boston Children's Hospital , Boston, Massachusetts.
authors: Peter Andrija
authors: PA
authors: Nigrovic
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .|5 Department of Internal Medicine, Taichung Veteran General Hospital , Chiayi Branch, Chiayi, Taiwan .
authors: Wen-Chen
authors: WC
authors: Chao
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .
authors: Wei-Zhi
authors: WZ
authors: Wang
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .
authors: George Chengkang
authors: GC
authors: Hsu
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .
authors: Yau-Sheng
authors: YS
authors: Tsai
authors: 1 Institute of Clinical Medicine, National Cheng Kung University College of Medicine , Tainan, Taiwan .|6 Department of Pediatrics, National Cheng Kung University Hospital , Tainan, Taiwan .
authors: Chi-Chang
authors: CC
authors: Shieh
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000473:pathology; D001168:Arthritis / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D008562:Membrane Glycoproteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014955:Wrist Joint / Q000187:drug effects / Q000473:pathology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D016207:Cytokines; D004151:Dipeptides; D053583:Interleukin-1beta; D007659:Ketones; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C057383:MDL 201053; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002401:Cathepsin B