Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice.

Abstract

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-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.

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-1β-mediated inflammation, accounting for the more severe arthritis in the absence of NOX2.

• Authors: Ya-Fang Huang, Pei-Chi Lo, Chia-Liang Yen, Peter Andrija Nigrovic, Wen-Chen Chao, Wei-Zhi Wang, George Chengkang Hsu, Yau-Sheng Tsai, Chi-Chang Shieh
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 23 Issue 12 Pg. 973-84 (Oct 20 2015) ISSN: 1557-7716 [Electronic] United States
• PMID: 25867281 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Caspase Inhibitors
• Cytokines
• Dipeptides
• Interleukin-1beta
• Ketones
• Membrane Glycoproteins
• Reactive Oxygen Species
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• MDL 201053
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• Cathepsin B

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Ankle Joint (drug effects, pathology)
• Arthritis (blood, metabolism, physiopathology)
• Caspase Inhibitors (pharmacology)
• Cathepsin B (antagonists & inhibitors)
• Cell Line
• Cytokines (metabolism)
• Dipeptides (pharmacology)
• Disease Models, Animal
• Fibroblasts (pathology)
• Humans
• Inflammation (pathology)
• Interleukin-1beta (metabolism)
• Ketones (pharmacology)
• Lung (cytology)
• Membrane Glycoproteins (genetics)
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases (genetics)
• Oxidation-Reduction (drug effects)
• Reactive Oxygen Species (metabolism)
• Wrist Joint (drug effects, pathology)