Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-beta Activity
AuthorXia, YC; Radwan, A; Keenan, CR; Langenbach, SY; Li, M; Radojicic, D; Londrigan, SL; Gualano, RC; Stewart, AG
Source TitlePLoS Pathogens
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sRadojicic, Danica; Xia, Yuxiu; Langenbach, Shenna; Londrigan, Sarah; Gualano, Rosa; Stewart, Alastair; Keenan, Christine; Li, Meina
AffiliationPharmacology and Therapeutics
Microbiology and Immunology
Document TypeJournal Article
CitationsXia, Y. C., Radwan, A., Keenan, C. R., Langenbach, S. Y., Li, M., Radojicic, D., Londrigan, S. L., Gualano, R. C. & Stewart, A. G. (2017). Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-beta Activity. PLOS PATHOGENS, 13 (1), https://doi.org/10.1371/journal.ppat.1006138.
Access StatusOpen Access
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-β (TGF-β) 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-β. In the current study, we examine the contribution of TGF-β 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-β expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-β 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-β.
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