title: Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.
abstract: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R.
  
  
  
  To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema.
  
  
  
  We used the gp130F/Fgenetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed.
  
  
  
  Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes.
  
  
  
  Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Saleela M
authors.initials: SM
authors.lastname: Ruwanpura
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.affiliation: 3 Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Lovisa F
authors.initials: LF
authors.lastname: Dousha
authors.affiliation: 3 Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Huei J
authors.initials: HJ
authors.lastname: Seow
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Sultan
authors.initials: S
authors.lastname: Alhayyani
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tate
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Virginie
authors.initials: V
authors.lastname: Deswaerte
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Brooks
authors.affiliation: 3 Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.|4 School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.affiliation: 5 Monash Lung and Sleep, Monash Medical Centre, Victoria, Australia; and.
authors.forename: Martin
authors.initials: M
authors.lastname: MacDonald
authors.affiliation: 6 Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|5 Monash Lung and Sleep, Monash Medical Centre, Victoria, Australia; and.
authors.forename: Paul T
authors.initials: PT
authors.lastname: King
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|5 Monash Lung and Sleep, Monash Medical Centre, Victoria, Australia; and.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Bardin
authors.affiliation: 3 Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.|4 School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.affiliation: 6 Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: 3 Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.affiliation: 1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|2 Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000494:pharmacology*; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: interleukin-6; mechanistic target of rapamycin complex 1; mouse models; pulmonary emphysema; trans-signaling