161: Novel role for interleukin-6 trans-signaling in the pathogenesis of pulmonary inflammation and emphysema

Abstract

Introduction Lung inflammation triggered by cigarette smoking is strongly linked to emphysema, a major component of the debilitating Chronic Obstructive Pulmonary Disease (COPD). Considering immune regulators are likely to influence emphysema susceptibility, we have recently shown that expression of the potent immunomodulatory cytokine interleukin (IL)-6 is consistently increased in emphysema patients, and increased IL-6 expression in a genetic mouse model for spontaneous emphysema (gp130 F / F ) drives the onset of lung disease [1] . Although IL-6 signals using 2 distinct modes, classical signalling via its membrane-bound IL-6 receptor (mIL-6R), and trans-signaling (TS) via a naturally-occurring soluble IL-6R (sIL-6R), the precise mechanism(s) by which IL-6 promotes emphysema remains to be elucidated. Methods The gp130 F / F emphysema mouse model was used to measure the gene and protein expression status of specific IL-6 signalling components, and genetic and therapeutic blockade of IL-6TS in these mice was employed to prove the specific role of IL-6TS in driving disease. Findings were validated in human lung tissue biopsies. Results sIL-6R production is elevated in the lungs of emphysematous mice, and is coincident with up-regulation of ADAM17 which is responsible for proteolytic cleavage of mIL-6R to produce sIL-6R. Transgenic over-expression of the IL-6TS antagonist sgp130Fc blocks the development of pulmonary inflammation and emphysema in gp130 F / F mice. Notably, IL-6TS-driven emphysema correlated with augmented alveolar cell apoptosis in gp130 F / F mice. Furthermore, we demonstrate that exposure of wild-type mice to cigarette smoke leads to excessive sIL-6R production and alveolar cell apoptosis, the latter of which is blocked by pre-treating mice with sgp130Fc. Finally, we also reveal that IL-6, ADAM17 and sIL-6R are up-regulated in human lung tissue from emphysema patients. Collectively, our data reveal that specific targeting of IL-6TS represents a new therapeutic strategy for emphysema/COPD.