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

Date Published: January 3, 2017

Publisher: Public Library of Science

Author(s): Yuxiu C. Xia, Asmaa Radwan, Christine R. Keenan, Shenna Y. Langenbach, Meina Li, Danica Radojicic, Sarah L. Londrigan, Rosa C. Gualano, Alastair G. Stewart, Matthias Johannes Schnell.


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.

Partial Text

Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are commonly associated with airway viral infection, including respiratory syncytial virus (RSV), human rhinovirus (RV) and influenza A virus (IAV) [1, 2]. RSV infection is a major cause of acute respiratory disease (i.e. bronchiolitis), especially in infants and the elderly [3–5]. Most children are infected by RSV at least once by 2 years of age [3]. RSV infection in children does not elicit long-term immunity, and the adaptive immunity following natural infection is poorly protective even in adults. Thus, re-infection occurs throughout life, even with the identical RSV strain [6, 7]. Severe RSV infection in infancy may result in Th2 and Th17-biased responses, that influence allergic airway inflammation[6]. Approximately 50% of the children who had severe RSV bronchiolitis were subsequently diagnosed with asthma [8, 9]. In addition to RSV, RV and IAV are also commonly detected in patients with asthma and COPD exacerbations [2, 10, 11].

Respiratory viral infection-induced acute bronchiolitis and asthma/COPD exacerbations are worldwide health problems, with a substantial disease burden in the young, the elderly, in adults with chronic lung disease and patients who are immunocompromised [3, 4]. Inhaled or oral glucocorticoids are standard treatments for asthma and COPD, but GCs are generally not effective for treating exacerbations of asthma and COPD, and other inflammatory complications of respiratory virus infection. In this study, we identified that endogenous TGF-β is expressed, induced TGF-β-like activity, increases PAI-1 expression in RSV, RV or IAV-infected bronchial epithelial cells, contributing to the viral infection-induced GC insensitivity. We also showed that treatment of epithelial cells with the anti-allergic agent tranilast reduced the expression and activity of TGF-β, and restored GC sensitivity (Fig 12).




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