Respiratory Syncytial Virus Represses Glucocorticoid Receptor-Mediated Gene Activation

Abstract

Respiratory syncytial virus (RSV) is a common cause of bronchiolitis in infants. Although antiinflammatory in nature, glucocorticoids have been shown to be ineffective in the treatment of RSV-induced bronchiolitis and wheezing. In addition, the effectiveness of glucocorticoids at inhibiting RSV-induced proinflammatory cytokine production in cell culture has been questioned. In this study, we have investigated the effect of RSV infection on glucocorticoid-induced gene activation in lung epithelium-derived cells. We show that RSV infection inhibits dexamethasone induction of three glucocorticoid receptor (GR)-regulated genes (glucocorticoid-inducible leucine zipper, FK506 binding protein, and MAPK phosphatase 1) in A549, BEAS-2B cells, and primary small airway epithelial cells. UV irradiation of the virus prevents this repression, suggesting that viral replication is required. RSV is known to activate the nuclear factor κB (NFκB) pathway, which is mutually antagonistic towards the GR pathway. However, specific inhibition of NFκB had no effect on the repression of GR-induced genes by RSV infection, indicating that RSV repression of GR is independent of NFκB. RSV infection of A549 cells does not alter GR protein levels or GR nuclear translocation but does reduce GR binding to the promoters of the glucocorticoid responsive genes analyzed in this study. Repression of GR by RSV infection may account for the apparent clinical ineffectiveness of glucocorticoids in RSV bronchiolitis therapy. In addition, this data adds to our previously published data suggesting that GR may be a general target for infectious agents. Identifying the mechanisms through which this suppression occurs may lead to the development of novel therapeutics.

Suppression of IRG-1 Reduces Inflammatory Cell Infiltration and Lung Injury in Respiratory Syncytial Virus Infection by Reducing Production of Reactive Oxygen Species

“…The infection is exquisitely restricted to the mucosa of the respiratory tract, since the virus does not normally replicate outside the bronchopulmonary tree. Although inflammatory mediators play a major role in the pathogenesis of RSV disease, glucocorticoids, anti-inflammatory in nature, have been shown to be ineffective in the treatment of RSV-induced bronchiolitis and wheezing (56)(57)(58). Several groups have recently shown ROS may be important regulators of RSV-induced cellular signaling and may play a fundamental role in the pathogenesis of RSVassociated lung injury due to oxidative stress and the production of inflammation mediators (23).…”

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β2-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

“…This may translate into improved clinical outcomes. Importantly, PDE inhibition will, in combination with LABAs, help maintain glucocorticoid-induced gene expression, a response that can be attenuated by inflammatory stimuli, respiratory viruses, cigarette smoke, and factors that promote airway remodeling (Hinzey et al, 2011;Rider et al, 2011Rider et al, , 2013Salem et al, 2012).…”

Role of Transcription Factors in the Pathogenesis of Asthma and COPD

“…Furthermore rhinovirus infection of asthmatic patients in vivo is associated with enhanced NF-κ B p65 nuclear expression in bronchial epithelial cell, increased NF-κ B p65 DNA binding in lung tissue and elevated levels of NF-κ B-regulated infl ammatory mediators (Bartlett et al, 2012). Finally, induction of infl ammatory mediators by respiratory syncytial virus (RSV) infection of primary human bronchial epithelial cells is also associated with NF-κ B activation (Hinzey et al, 2011).…”

“…This may explain why patients with steroid-resistant asthma are not resistant to the endocrine and metabolic effects of glucocorticoids, and thus develop the drug ' s systemic side effects. The situation is probably more complex as different stimuli, including infections and T-cell co-stimulation, can induce a relative glucocorticoid insensitivity in a celland context-dependent manner (Galliher-Beckley et al, 2011;Goleva et al, 2002;Hinzey et al, 2011;Tsitoura & Rothman, 2004) via distinct mechanisms.…”