Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice

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 mutationing p130 that deregulates intracellular signalingby 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 (gp130F/F:IL-6 ^-/-) prevented emphysema. By contrast, the genetic ablation of receptor signalingvia IL-11, which like IL-6 signals via a gp130homodimerand 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. Wepropose that the discrete targeting of IL-6 signaling mayprovide an effective therapeutic strategy against human lung disease.