IL-6/Stat3-driven pulmonary inflammation, but not emphysema, is dependent on interleukin-17A in mice

Saleela Madhavi Ruwanpura, Louise McLeod, Gavin De Carle Brooks, Steven Bozinovski, Ross Vlahos, Anthony Longano, Philip G Bardin, Gary Anderson, Brendan John Jenkins

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Pulmonary emphysema is linked to T cell-mediated autoimmune inflammation, although the pathogenic role of specific pro-inflammatory cytokines remains unclear. The Th17 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 (Stat)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 Th17-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 Th17-related factors was augmented compared with gp130+/+ (wild-type), gp130(F/F) : Il6-/- and gp130(F/F) : Stat3-/+ mice displaying normalized Stat3 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 Tnfalpha; as well as Il6 and the Stat3-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/Stat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL-17A may alleviate pulmonary inflammatory-related diseases.
Original languageEnglish
Pages (from-to)419 - 427
Number of pages9
JournalRespirology
Volume19
Issue number3
DOIs
Publication statusPublished - 2014

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