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Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice
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)-...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mary Ann Liebert, Inc.
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624247/ https://www.ncbi.nlm.nih.gov/pubmed/25867281 http://dx.doi.org/10.1089/ars.2014.6136 |
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author | Huang, Ya-Fang Lo, Pei-Chi Yen, Chia-Liang Nigrovic, Peter Andrija Chao, Wen-Chen Wang, Wei-Zhi Hsu, George Chengkang Tsai, Yau-Sheng Shieh, Chi-Chang |
author_facet | Huang, Ya-Fang Lo, Pei-Chi Yen, Chia-Liang Nigrovic, Peter Andrija Chao, Wen-Chen Wang, Wei-Zhi Hsu, George Chengkang Tsai, Yau-Sheng Shieh, Chi-Chang |
author_sort | Huang, Ya-Fang |
collection | PubMed |
description | 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. Antioxid. Redox Signal. 23, 973–984. |
format | Online Article Text |
id | pubmed-4624247 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Mary Ann Liebert, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-46242472015-11-05 Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice Huang, Ya-Fang Lo, Pei-Chi Yen, Chia-Liang Nigrovic, Peter Andrija Chao, Wen-Chen Wang, Wei-Zhi Hsu, George Chengkang Tsai, Yau-Sheng Shieh, Chi-Chang Antioxid Redox Signal Original Research Communications 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. Antioxid. Redox Signal. 23, 973–984. Mary Ann Liebert, Inc. 2015-10-20 /pmc/articles/PMC4624247/ /pubmed/25867281 http://dx.doi.org/10.1089/ars.2014.6136 Text en © Ya-Fang Huang et al. 2015; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited |
spellingShingle | Original Research Communications Huang, Ya-Fang Lo, Pei-Chi Yen, Chia-Liang Nigrovic, Peter Andrija Chao, Wen-Chen Wang, Wei-Zhi Hsu, George Chengkang Tsai, Yau-Sheng Shieh, Chi-Chang Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice |
title | Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice |
title_full | Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice |
title_fullStr | Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice |
title_full_unstemmed | Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice |
title_short | Redox Regulation of Pro-IL-1β Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice |
title_sort | redox regulation of pro-il-1β processing may contribute to the increased severity of serum-induced arthritis in nox2-deficient mice |
topic | Original Research Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624247/ https://www.ncbi.nlm.nih.gov/pubmed/25867281 http://dx.doi.org/10.1089/ars.2014.6136 |
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