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

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    Author
    Xia, YC; Radwan, A; Keenan, CR; Langenbach, SY; Li, M; Radojicic, D; Londrigan, SL; Gualano, RC; Stewart, AG
    Date
    2017-01-01
    Source Title
    PLoS Pathogens
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Radojicic, Danica; Xia, Yuxiu; Langenbach, Shenna; Londrigan, Sarah; Gualano, Rosa; Stewart, Alastair; Keenan, Christine; Li, Meina
    Affiliation
    Pharmacology and Therapeutics
    Microbiology and Immunology
    Metadata
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    Document Type
    Journal Article
    Citations
    Xia, 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 Status
    Open Access
    URI
    http://hdl.handle.net/11343/257975
    DOI
    10.1371/journal.ppat.1006138
    Abstract
    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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