ORIGINAL RESEARCH COMMUNICATION Redox Regulation of Pro-IL-1b Processing May Contribute to the Increased Severity of Serum-Induced Arthritis

Aims: 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 andNADPHoxidase 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/p47phox component of NOX2. The levels of interleukin-1b (IL-1b) and IL-6 in inflamed joints were higher in Ncf1- /- than in controls. Antagonists of tumor necrosis factor-a (TNFa) and IL-1b were equally effective in suppressing arthritis in wild-type mice, while IL-1b blockade was more effective than TNFa 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 pro-teolytically process pro-IL-1b to its active form and this activity was suppressed by ROS. Innovation: 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.Conclusion:Our results suggest that ROS act as a negative feedback to constrain IL-1b-mediated inflammation, accounting for themore severe arthritis in the absence of NOX2. Antioxid. Redox Signal. 23, 973–984