Interleukin-6 Promotes Pulmonary Emphysema Associated with Apoptosis in Mice

• DOI: 10.1165/rcmb.2010-0462oc
• Publication Date: 2011-02-05T05:20:40Z
• Authors: Saleela M. Ruwanpura; Louise McLeod; Alistair Miller; Jessica Jones; Steven Bozinovski; Ross Vlahos; Matthias Ernst; Jane Armes; Philip G. Bardin; Gary P. Anderson; Brendan J. Jenkins
• Keywords: 0301 basic medicine; Aging; Time Factors; 610; Apoptosis; 1308 Clinical Biochemistry; 1307 Cell Biology; gp130; Mice; 03 medical and health sciences; Smoke; 1312 Molecular Biology; Cytokine Receptor gp130; Animals; Mice, Knockout; IL-6; Interleukin-6; Smoking; Up-Regulation; 3. Good health; Pulmonary Alveoli; Pulmonary Emphysema; 2740 Pulmonary and Respiratory Medicine; Cytokines; Receptor; Signal Transduction

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.