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

MS Wilson, SK Madala, TR Ramalingam… - Journal of Experimental …, 2010 - rupress.org
MS Wilson, SK Madala, TR Ramalingam, BR Gochuico, IO Rosas, AW Cheever, TA Wynn
Journal of Experimental Medicine, 2010rupress.org
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 …
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.
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