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. 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.NEW & NOTEWORTHY 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.