| Title | Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-beta Activity. | ||
| Author | Xia, Yuxiu C; Radwan, Asmaa; Keenan, Christine R; Langenbach, Shenna Y; Li, Meina; Radojicic, Danica; Londrigan, Sarah L; Gualano, Rosa C; Stewart, Alastair G | ||
| Journal | PLoS Pathog | Publication Year/Month | 2017-Jan |
| PMID | 28046097 | PMCID | PMC5234851 |
| Affiliation + expend | 1.Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia. | ||
Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-beta (TGF-beta) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-beta. In the current study, we examine the contribution of TGF-beta activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-beta expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFbetaRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-beta activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-beta.