title: Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice.
abstract: The IL-6 cytokine family, which signals via the shared gp130 coreceptor, is linked with the pathogenesis of emphysema. However, the definitive mechanisms by which these cytokines cause emphysema remain ill-defined. We took an in vivo genetic complementation approach to identify the specific IL-6 cytokine family members and gp130-regulated cellular processes that cause emphysema. We used gp130(F/F) mice homozygous for a subtle knock-in mutation in gp130 that deregulates intracellular signaling by the IL-6 cytokine family. The gp130(F/F) mice spontaneously develop emphysema by age 6 months. Within the IL-6 cytokine family, only IL-6 was significantly up-regulated in the lungs of gp130(F/F) mice, and the genetic targeting of IL-6 in gp130(F/F) mice (gp130(F/F):IL-6(-/-)) prevented emphysema. By contrast, the genetic ablation of receptor signaling via IL-11, which like IL-6 signals via a gp130 homodimer and uses the same signaling machinery, failed to ameliorate emphysema in gp130(F/F) mice. Among the disease-associated processes examined, emphysema strongly correlated with elevated alveolar cell apoptosis. Acute (4-day) exposure to cigarette smoke (CS) further augmented the expression of IL-6 in lungs of gp130(F/F) mice, and subchronic (6-week) exposure to CS exacerbated emphysematous and apoptotic changes in the lungs of gp130(F/F) but not gp130(F/F): IL-6(-/-) mice. IL-6 is the main causative agent of IL-6 cytokine family-induced emphysema, and operates to induce apoptosis in the lung. We propose that the discrete targeting of IL-6 signaling may provide an effective therapeutic strategy against human lung disease.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton 3168, 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: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Jane
authors.initials: J
authors.lastname: Armes
authors.forename: Philip G
authors.initials: PG
authors.lastname: Bardin
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D012906:Smoke; D050822:Cytokine Receptor gp130