| First Author | Huang YF | Year | 2015 |
| Journal | Antioxid Redox Signal | Volume | 23 |
| Issue | 12 | Pages | 973-84 |
| PubMed ID | 25867281 | Mgi Jnum | J:329667 |
| Mgi Id | MGI:6760223 | Doi | 10.1089/ars.2014.6136 |
| Citation | Huang YF, et al. (2015) Redox Regulation of Pro-IL-1beta Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice. Antioxid Redox Signal 23(12):973-84 |
| abstractText | 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 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-1beta (IL-1beta) and IL-6 in inflamed joints were higher in Ncf1(-/-) than in controls. Antagonists of tumor necrosis factor-alpha (TNFalpha) and IL-1beta were equally effective in suppressing arthritis in wild-type mice, while IL-1beta blockade was more effective than TNFalpha 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-1beta 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-1beta-mediated inflammation, accounting for the more severe arthritis in the absence of NOX2. |
