%0 Journal Article
%T Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-¦Â Activity
%A Alastair G. Stewart
%A Asmaa Radwan
%A Christine R. Keenan
%A Danica Radojicic
%A Meina Li
%A Rosa C. Gualano
%A Sarah L. Londrigan
%A Shenna Y. Langenbach
%A Yuxiu C. Xia
%J -
%D 2017
%R 10.1371/journal.ppat.1006138
%X 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-¦Â (TGF-¦Â) 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-¦Â. In the current study, we examine the contribution of TGF-¦Â 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-¦Â expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGF¦ÂRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-¦Â 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-¦Â
%K Respiratory infections
%K Gene expression
%K Viral transmission and infection
%K Epithelial cells
%K Influenza A virus
%K Chronic obstructive pulmonary disease
%K Small interfering RNAs
%K Cytokines
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006138