Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent

J Exp Med. 2010 Mar 15;207(3):535-52. doi: 10.1084/jem.20092121. Epub 2010 Feb 22.

Abstract

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 gammadelta(+) T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a(-/-) mice confirmed an essential role for IL-17A. Mechanistically, using ifngamma(-/-), il10(-/-), il10(-/-)il12p40(-/-), and il10(-/-)il17a(-/-) mice and TGF-beta blockade, we demonstrate that IL-17A-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced IL-17A production was also TGF-beta dependent, and recombinant IL-17A-mediated fibrosis required TGF-beta, suggesting cooperative roles for IL-17A and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by IL-1beta, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1beta 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bleomycin / adverse effects
  • CD4-Positive T-Lymphocytes / immunology
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / immunology
  • Interleukin-12 Subunit p40 / immunology
  • Interleukin-13 / immunology
  • Interleukin-17 / deficiency
  • Interleukin-17 / immunology
  • Interleukin-17 / physiology*
  • Interleukin-1beta / adverse effects*
  • Interleukin-1beta / biosynthesis
  • Lung / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / immunology
  • Schistosoma mansoni / immunology
  • Schistosomiasis mansoni / complications

Substances

  • Interleukin-12 Subunit p40
  • Interleukin-13
  • Interleukin-17
  • Interleukin-1beta
  • Bleomycin
  • Interleukin-10
  • Interferon-gamma