• Am. J. Respir. Cell Mol. Biol. · Oct 2011

    Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice.

    • Saleela M Ruwanpura, Louise McLeod, Alistair Miller, Jessica Jones, Steven Bozinovski, Ross Vlahos, Matthias Ernst, Jane Armes, Philip G Bardin, Gary P Anderson, and Brendan J Jenkins.
    • Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton 3168, Victoria, Australia.
    • Am. J. Respir. Cell Mol. Biol. 2011 Oct 1; 45 (4): 720-30.

    AbstractThe 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.

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