title: Deregulated Stat3 signaling dissociates pulmonary inflammation from emphysema in gp130 mutant mice.
abstract: Interleukin (IL)-6 is a potent immunomodulatory cytokine that is associated with emphysema, a major component of chronic obstructive pulmonary disease (COPD). IL-6 signaling via the gp130 coreceptor is coupled to multiple signaling pathways, especially the latent transcription factor signal transducer and activator of transcription (Stat)3. However, the pathological role of endogenous gp130-dependent Stat3 activation in emphysema is ill defined. To elucidate the role of the IL-6/gp130/Stat3 signaling axis in the cellular and molecular pathogenesis of emphysema, we employed a genetic complementation strategy using emphysematous gp130(F/F) mice displaying hyperactivation of endogenous Stat3 that were interbred with mice to impede Stat3 activity. Resected human lung tissue from patients with COPD and COPD-free individuals was also evaluated by immunohistochemistry. Genetic reduction of Stat3 hyperactivity in gp130(F/F):Stat3(-/+) mice prevented lung inflammation and excessive protease activity; however, emphysema still developed. In support of these findings, Stat3 activation levels in human lung tissue correlated with the extent of pulmonary inflammation but not airflow obstruction in COPD. Furthermore, COPD lung tissue displayed increased levels of IL-6 and apoptotic alveolar cells, supporting our previous observation that increased endogenous IL-6 expression in the lungs of gp130(F/F) mice contributes to emphysema by promoting alveolar cell apoptosis. Collectively, our data suggest that IL-6 promotes emphysema via upregulation of Stat3-independent apoptosis, whereas IL-6 induction of lung inflammation occurs via Stat3. We propose that while discrete targeting of Stat3 may alleviate pulmonary inflammation, global targeting of IL-6 potentially represents a therapeutically advantageous approach to combat COPD phenotypes where emphysema predominates.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash Univ., Clayton, Victoria, Australia.
authors.forename: Saleela M
authors.initials: SM
authors.lastname: Ruwanpura
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.forename: Alistair
authors.initials: A
authors.lastname: Miller
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.forename: Anthony
authors.initials: A
authors.lastname: Longano
authors.forename: Philip G
authors.initials: PG
authors.lastname: Bardin
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D004646:Emphysema / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130