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Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells

Novel Role of Interferon Regulatory Factor-1

¹ Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ² Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom

Correspondence and requests for reprints should be addressed to Omar Tliba, Ph.D., Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, 125 South 31st Street, TRL Suite 1200, Room 1214, Philadelphia, PA 19104-3403. E-mail: omartlib{at}mail.med.upenn.edu

We have previously shown that long-term treatment of airway smooth muscle (ASM) cells with a combination of TNF- and IFN- impaired steroid anti-inflammatory action through the up-regulation of glucocorticoid receptor beta isoform (GRβ) (Mol Pharmacol 2006;69:588–596). We here found that steroid actions could also be suppressed by short-term exposure of ASM cells to TNF- and IFN- (6 h) as shown by the abrogated glucocorticoid responsive element (GRE)-dependent gene transcription; surprisingly, neither GR nuclear translocation nor GRβ expression was affected by cytokine mixture. The earlier induction of CD38, a molecule recently involved in asthma, seen with TNF- and IFN- combination but not with cytokine alone, was also completely insensitive to steroid pretreatment. Chromatin-immunoprecipitation (IP) and siRNA strategies revealed not only increased binding of interferon regulatory factor 1 (IRF-1) transcription factor to CD38 promoter, but also its implication in regulating CD38 gene transcription. Interestingly, the capacity of fluticasone to completely inhibit TNF-–induced IRF-1 expression, IRF-1 DNA binding, and transactivation activities was completely lost in cells exposed to TNF- and IFN- in combination. This early steroid dysfunction seen with cytokine combination could be reproduced by enhancing IRF-1 cellular levels using constitutively active IRF-1, which dose-dependently inhibited GRE-dependent gene transcription. Consistently, reducing IRF-1 cellular levels using siRNA approach significantly restored steroid transactivation activities. Collectively, our findings demonstrate for the first time that IRF-1 is a novel alternative GRβ-independent mechanism mediating steroid dysfunction induced by pro-asthmatic cytokines, in part via the suppression of GR activities.

Key Words: transcription factor • glucocorticoid • inflammation • asthma • mesenchymal cells

CLINICAL RELEVANCE This research uncovered a novel molecule associated with pro-asthmatic signals involved in steroid resistance. Therefore, our findings will likely bring new insight into the development of novel therapeutic treatment of patients with steroid resistance.