Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Wilson, Mark S., Madala, Satish K., Ramalingam, Thirumalai R., Gochuico, Bernadette R., Rosas, Ivan O., Cheever, Allen W., Wynn, Thomas A.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
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
_version_ 1782178930808061952
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
work_keys_str_mv AT wilsonmarks bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent
AT madalasatishk bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent
AT ramalingamthirumalair bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent
AT gochuicobernadetter bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent
AT rosasivano bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent
AT cheeverallenw bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent
AT wynnthomasa bleomycinandil1bmediatedpulmonaryfibrosisisil17adependent