Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/14780
Title: Cytokines induce an early steroid resistance in airway smooth muscle cells: novel role of interferon regulatory factor-1.
Authors: Tliba, O
Damera, G
Banerjee, A
Gu, S
Baidouri, H
Keslacy, S
Amrani, Y
First Published: Apr-2008
Citation: AM J RESPIR CELL MOL BIOL, 2008, 38 (4), pp. 463-472
Abstract: We have previously shown that long-term treatment of airway smooth muscle (ASM) cells with a combination of TNF-alpha and IFN-gamma impaired steroid anti-inflammatory action through the up-regulation of glucocorticoid receptor beta isoform (GRbeta) (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-alpha and IFN-gamma (6 h) as shown by the abrogated glucocorticoid responsive element (GRE)-dependent gene transcription; surprisingly, neither GRalpha nuclear translocation nor GRbeta expression was affected by cytokine mixture. The earlier induction of CD38, a molecule recently involved in asthma, seen with TNF-alpha and IFN-gamma 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-alpha-induced IRF-1 expression, IRF-1 DNA binding, and transactivation activities was completely lost in cells exposed to TNF-alpha and IFN-gamma 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 GRbeta-independent mechanism mediating steroid dysfunction induced by pro-asthmatic cytokines, in part via the suppression of GRalpha activities.
DOI Link: 10.1165/rcmb.2007-0226OC
eISSN: 1535-4989
Links: http://hdl.handle.net/2381/14780
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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