Abstract | AIMS: 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)
|