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.

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

“…Thus, partial abrogation of TGF-β 1 activity presents a clinically tractable approach to the treatment of fibrosis ( LaChapelle et al, 2018 ). Our efforts to identify the mechanism of TGF-β-induced glucocorticoid insensitivity ( Salem et al, 2012 ; Keenan et al, 2014 ; Xia et al, 2017 ) lead to a comprehensive literature review that revealed a little-known connection between TGF-β 1 signaling and casein kinase (CK) activity ( Hall et al, 1996 ). CK1ε physically interacts with Smad3 to mediate some TGF-β signals, including upregulation of the fibrogen, plasminogen-activator inhibitor-1 ( Waddell et al, 2004 ).…”

A Non-canonical Pathway with Potential for Safer Modulation of Transforming Growth Factor-β1 in Steroid-Resistant Airway Diseases

“…To investigate the global impact of TGF-β1 on GC gene regulation, we conducted RNA-seq analyses of extracts of BEAS-2B cells (n = 3) incubated with TGF-β1 (40 pM), and then exposed to dexamethasone (Dex, 30 nM), using concentrations previously established as maximally effective (Keenan et al., 2014, Salem et al., 2012, Xia et al., 2017). Genes influenced by TGF-β1 alone by more than 2-fold and those with smaller but significant changes (applying a Benjamini and Hochberg [BH] false discovery rate [FDR] < 0.05) were filtered from the analyzed set to avoid the confounding influence of direct TGF-β1 gene regulation.…”

“…However, the insensitivity induced by transforming growth factor β1 (TGF-β1) demands most attention because of its extraordinary capacity at picomolar concentrations to ablate GC anti-inflammatory activity in airway and lung epithelial cells (Keenan et al., 2014, Salem et al., 2012). Moreover, we have recently identified that viral infection of human bronchial epithelial cells impairs GC anti-inflammatory activity through the induction of TGF-β1 activity (Xia et al., 2017).…”

Plasmodium berghei NK65 in Combination with IFN-γ Induces Endothelial Glucocorticoid Resistance via Sustained Activation of p38 and JNK

“…TNF downregulates the levels of hepatic GR in vivo , whereas TGF-β exposure (before challenge with IL-1 α ) reduces GR levels in A549 cells ( 64 , 65 ). However, TGF-β induced by respiratory syncytial virus fails to downregulate GR levels in human airway epithelial cells ( 66 ). Proteasomal degradation of GR reduces its levels and was proposed to cause GC resistance in endothelial cells ( 32 , 33 ).…”