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Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent
Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839145/ https://www.ncbi.nlm.nih.gov/pubmed/20176803 http://dx.doi.org/10.1084/jem.20092121 |
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author | Wilson, Mark S. Madala, Satish K. Ramalingam, Thirumalai R. Gochuico, Bernadette R. Rosas, Ivan O. Cheever, Allen W. Wynn, Thomas A. |
author_facet | Wilson, Mark S. Madala, Satish K. Ramalingam, Thirumalai R. Gochuico, Bernadette R. Rosas, Ivan O. Cheever, Allen W. Wynn, Thomas A. |
author_sort | Wilson, Mark S. |
collection | PubMed |
description | Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4(+) and γδ(+) T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a(−/−) mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ(−/−), il10(−/−), il10(−/−)il12p40(−/−), and il10(−/−)il17a(−/−) mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis. |
format | Text |
id | pubmed-2839145 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28391452010-09-15 Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent Wilson, Mark S. Madala, Satish K. Ramalingam, Thirumalai R. Gochuico, Bernadette R. Rosas, Ivan O. Cheever, Allen W. Wynn, Thomas A. J Exp Med Article Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4(+) and γδ(+) T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a(−/−) mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ(−/−), il10(−/−), il10(−/−)il12p40(−/−), and il10(−/−)il17a(−/−) mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis. The Rockefeller University Press 2010-03-15 /pmc/articles/PMC2839145/ /pubmed/20176803 http://dx.doi.org/10.1084/jem.20092121 Text en © 2010 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Wilson, Mark S. Madala, Satish K. Ramalingam, Thirumalai R. Gochuico, Bernadette R. Rosas, Ivan O. Cheever, Allen W. Wynn, Thomas A. Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent |
title | Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent |
title_full | Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent |
title_fullStr | Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent |
title_full_unstemmed | Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent |
title_short | Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent |
title_sort | bleomycin and il-1β–mediated pulmonary fibrosis is il-17a dependent |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839145/ https://www.ncbi.nlm.nih.gov/pubmed/20176803 http://dx.doi.org/10.1084/jem.20092121 |
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