Inhibition of IFN-γ-dependent antiviral airway epithelial defense by cigarette smoke

Modestos A Modestou,Lori J Manzel,Sherif El-Mahdy,Dwight C Look

doi:10.1186/1465-9921-11-64

Abstract

BackgroundAlthough individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on lung defense are incompletely understood. Because airway epithelial cell responses to type II interferon (IFN) are critical in regulation of defense against many respiratory viral infections, we hypothesized that cigarette smoke has inhibitory effects on IFN-γ-dependent antiviral mechanisms in epithelial cells in the airway.MethodsPrimary human tracheobronchial epithelial cells were first treated with cigarette smoke extract (CSE) followed by exposure to both CSE and IFN-γ. Epithelial cell cytotoxicity and IFN-γ-induced signaling, gene expression, and antiviral effects against respiratory syncytial virus (RSV) were tested without and with CSE exposure.ResultsCSE inhibited IFN-γ-dependent gene expression in airway epithelial cells, and these effects were not due to cell loss or cytotoxicity. CSE markedly inhibited IFN-γ-induced Stat1 phosphorylation, indicating that CSE altered type II interferon signal transduction and providing a mechanism for CSE effects. A period of CSE exposure combined with an interval of epithelial cell exposure to both CSE and IFN-γ was required to inhibit IFN-γ-induced cell signaling. CSE also decreased the inhibitory effect of IFN-γ on RSV mRNA and protein expression, confirming effects on viral infection. CSE effects on IFN-γ-induced Stat1 activation, antiviral protein expression, and inhibition of RSV infection were decreased by glutathione augmentation of epithelial cells using N-acetylcysteine or glutathione monoethyl ester, providing one strategy to alter cigarette smoke effects.ConclusionsThe results indicate that CSE inhibits the antiviral effects of IFN-γ, thereby presenting one explanation for increased susceptibility to respiratory viral infection in individuals exposed to cigarette smoke.

Highlights

Individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on lung defense are incompletely understood
Human airway epithelial cells are an important target for respiratory viral infection, and epithelial responses to interferons are critical for antiviral defense
Pretreatment of human tracheobronchial epithelial (hTBE) cells with cigarette smoke extract (CSE) for 4 hours followed by addition of CSE during IFN-γ treatment inhibited the induction of the adhesive protein for leukocytes ICAM-1 seen with IFN-γ treatment for 20 hours (Figure 1A) or 8

Summary

Introduction

Individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on lung defense are incompletely understood. Because airway epithelial cell responses to type II interferon (IFN) are critical in regulation of defense against many respiratory viral infections, we hypothesized that cigarette smoke has inhibitory effects on IFN-γ-dependent antiviral mechanisms in epithelial cells in the airway. A growing body of evidence indicates that cigarette smoke exposure increases susceptibility to viral (and bacterial) respiratory infection. Individuals that actively smoke cigarettes have an increased incidence and longer duration of respiratory infection [4,5]. Available information indicates that cigarette smoke increases the incidence, duration, and/or severity of respiratory viral infection. Mechanisms responsible for the effects of cigarette smoke on lung defense are incompletely understood

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