title: Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-β Activity.
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.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yuxiu C
authors.identifier: 0000-0003-0067-8084
authors.initials: YC
authors.lastname: Xia
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Asmaa
authors.initials: A
authors.lastname: Radwan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Keenan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Shenna Y
authors.initials: SY
authors.lastname: Langenbach
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Meina
authors.initials: M
authors.lastname: Li
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Danica
authors.identifier: 0000-0003-0353-3702
authors.initials: D
authors.lastname: Radojicic
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Londrigan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Rosa C
authors.initials: RC
authors.lastname: Gualano
authors.affiliation: Lung Health Research Centre, Department of Pharmacology & Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Stewart
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D001249:Asthma / Q000473:pathology* / Q000821:virology; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D004149:Dioxoles / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000502:physiology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000821:virology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D009980:Influenza A virus; D007251:Influenza, Human / Q000821:virology; D010850:Picornaviridae Infections / Q000821:virology; D011070:Poly I-C / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology* / Q000821:virology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D020545:Respiratory Mucosa / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000821:virology; D012136:Respiratory Syncytial Viruses; D012229:Rhinovirus; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D001549:Benzamides; D004149:Dioxoles; D005938:Glucocorticoids; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C012293:tranilast; D011070:Poly I-C