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

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. Transforming growth factor β (TGF-β), a pleiotropic cytokine, is a modifier of CF lung disease; its mechanism of action in CF is unclear. Previous studies have shown that TGF-β induces interleukin-6 (IL-6) secretion from lung epithelium, which may drive worse pulmonary outcomes in CF and other lung diseases. However, the nature of the TGF-β/IL-6 relationship in CF is not fully understood. In this study, we demonstrated that TGF-β and IL-6 concentrations were positively associated in bronchoalveolar lavage fluid from children with CF. Furthermore, pulmonary TGF-β 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 phosphoinositide 3-kinase (PI3K) signaling after TGF-β exposure. In wild-type airway epithelium, TGF-β exposure and cystic fibrosis transmembrane conductance regulator (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 TGF-β 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. The etiology of IL-6 oversecretion in cystic fibrosis (CF) is unclear, as is the mechanism of CF lung disease modification by TGF-β. We show that TGF-β induces IL-6 oversecretion in human and mouse models of CF. In mechanistic studies, we further demonstrate that loss of CFTR function drives increased IL-6 secretion via the PI3K pathway downstream of TGF-β. Treatment of CF airway epithelial cells with a CFTR modulator rescues this IL-6 oversecretion.