Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-β Activity

PLoS Pathogens

Sarah L. Londrigan¹  Rosa C. Gualano²  Alastair G. Stewart²  Asmaa Radwan²  Christine R. Keenan²  Yuxiu C. Xia²  Danica Radojicic²  Shenna Y. Langenbach²  Meina Li² 

[1] Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia;Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia

关键词: Respiratory infections;    Gene expression;    Viral transmission;    infection;    Epithelial cells;    Influenza A virus;    Chronic obstructive pulmonary disease;    Small interfering RNAs;    Cytokines;   

DOI  :  10.1371/journal.ppat.1006138

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY