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IL‐6/Stat3‐driven pulmonary inflammation, but not emphysema, is dependent on interleukin‐17 A in mice
Author(s) -
Ruwanpura Saleela M.,
McLeod Louise,
Brooks Gavin D.,
Bozinovski Steven,
Vlahos Ross,
Longano Anthony,
Bardin Philip G.,
Anderson Gary P.,
Jenkins Brendan J.
Publication year - 2014
Publication title -
respirology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 85
eISSN - 1440-1843
pISSN - 1323-7799
DOI - 10.1111/resp.12243
Subject(s) - inflammation , glycoprotein 130 , interleukin 17 , medicine , immunology , stat3 , stat protein , cxcl1 , cd43 , cytokine , interleukin 23 , interleukin 6 , biology , chemokine , signal transduction , immunohistochemistry , microbiology and biotechnology , cd20
Abstract Background and objective Pulmonary emphysema is linked to T cell‐mediated autoimmune inflammation, although the pathogenic role of specific pro‐inflammatory cytokines remains unclear. The T h17 type response, characterized by the production of the cytokine interleukin ( IL )‐ 17A , is modulated in part by the IL ‐6/signal transducer and activator of transcription ( S tat)3 signalling axis and is associated with numerous autoimmune diseases. We therefore evaluated a causal role for IL ‐ 17A in the IL ‐6‐driven gp130 F / F mouse model for spontaneous pulmonary inflammation and emphysema. Methods The expression of T h17‐related factors was quantified in the lungs of gp130 F / F mice and emphysematous patients, and the degree of pulmonary inflammation and emphysema was measured in gp130 F / F : Il17a −/− mice by immunohistochemistry, stereology and respiratory mechanics. Results In gp130 F / F mice, lung gene expression of Il17a and other T h17‐related factors was augmented compared with gp130 +/+ (wild‐type), gp130 F / F : Il6 −/− and gp130 F / F : Stat3 −/+ mice displaying normalized S tat3 activity and no lung inflammation. Importantly, genetic ablation of Il17a in gp130 F / F : Il17a −/− mice prevented lung inflammation; however, emphysema still developed. Additionally, messenger RNA expression of inflammatory genes Cxcl1 , Cxcl2 , Ccl2 and Tnfα ; as well as Il6 and the S tat3‐target gene, Socs3 , were upregulated in the lungs of gp130 F / F mice compared with gp130 F / F : Il17a −/− and gp130 +/+ mice. Consistent with these findings, augmented IL17A expression was observed in emphysema patients presenting with inflammation compared with inflammation‐free individuals. Conclusions Collectively, our data suggest that the integration of IL ‐ 17A into the IL ‐6/ S tat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL ‐ 17A may alleviate pulmonary inflammatory‐related diseases.