title: IL-6/Stat3-driven pulmonary inflammation, but not emphysema, is dependent on interleukin-17A in mice.
abstract: OBJECTIVE
  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 Tnfα; 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.
authors: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors: Saleela M
authors: SM
authors: Ruwanpura
authors: Louise
authors: L
authors: McLeod
authors: Gavin D
authors: GD
authors: Brooks
authors: Steven
authors: S
authors: Bozinovski
authors: Ross
authors: R
authors: Vlahos
authors: Anthony
authors: A
authors: Longano
authors: Philip G
authors: PG
authors: Bardin
authors: Gary P
authors: GP
authors: Anderson
authors: Brendan J
authors: BJ
authors: Jenkins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D011014:Pneumonia / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D050796:STAT3 Transcription Factor
keywords: emphysema; inflammation; interleukin-17; mouse model; signal transducer and activator of transcription 3