TGFβ induces excessive pulmonary IL-6 secretion in cystic fibrosis via PI3K.

Abstract

Cystic Fibrosis (CF) is characterized by impaired mucociliary clearance and pulmonary infections. Accumulating evidence suggests that fundamentally abnormal inflammatory responses also contribute to CF pathology. TGFβ, a pleiotropic cytokine, is a modifier of CF lung disease; its mechanism of action in CF is unclear. Previous studies have shown that TGFβ induces IL-6 secretion from lung epithelium, which may drive worse pulmonary outcomes in CF and other lung diseases. However, the nature of the TGFβ/IL-6 relationship in CF is not fully understood. In this study, we demonstrated that TGFβ and IL-6 concentration were positively associated in bronchoalveolar lavage fluid from children with CF. Furthermore, pulmonary TGFβ exposure in a CF mouse model induced heightened IL-6 secretion when compared with non-CF mice. CF airway epithelial cells had increased IL-6 secretion and PI3K signaling after TGFβ exposure. In wild type airway epithelium, TGFβ exposure and CFTR inhibition synergistically provoked IL-6 secretion. Restoration of CFTR function by a CFTR modulator and inhibition of PI3K signaling both normalized IL-6 secretion from CF airway epithelial cells. These data indicate that TGFβ drives abnormal IL-6 secretion via the PI3K pathway in the CF airway, demonstrating an inherent inflammatory abnormality in CF and suggesting potential therapeutic targets.