Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/15174
Title: Inhibition of tumor necrosis factor-alpha-inducible inflammatory genes by interferon-gamma is associated with altered nuclear factor-kappaB transactivation and enhanced histone deacetylase activity.
Authors: Keslacy, S
Tliba, O
Baidouri, H
Amrani, Y
First Published: Feb-2007
Citation: MOL PHARMACOL, 2007, 71 (2), pp. 609-618
Abstract: Airway smooth muscle (ASM) cells can act as effector cells in the initiation and/or perpetuation of airway inflammation in asthma by producing various inflammatory chemokines or cytokines. Previous studies from our laboratory and others showed that the combination of tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) or endogenous IFNbeta results in a synergistic induction of various pro-inflammatory genes, including CD38 and regulated upon activation normal T-cell expressed and secreted (RANTES), in ASM cells. In contrast to these studies, we found that IFNgamma (1000 U/ml) markedly inhibited TNFalpha-induced expression of interleukin (IL)-6, IL-8, and eotaxin by 66.29+/-3.33, 43.86+/-7.11, and 63.25+/-6.46%, respectively. These genes were also found to be NF-kappaB-dependent in that TNFalpha-induced expression of IL-6, IL-8, and eotaxin was dose-dependently inhibited by the selective IKKbeta inhibitor 4-(2'-aminoethyl)amino-1,8-dimethylimidazo[1,2-a]quinoxaline (BMS-345541) (1-30 microM). Using a luciferase reporter construct containing kappaB sites, we found that IFNgamma (10-1000 U/ml) inhibits NF-kappaB-dependent gene transcription in a dose-dependent manner. Moreover, IFNgamma failed to affect TNFalpha-induced IkappaKbeta phosphorylation or IkappaB degradation as well as nuclear NF-kappaB/DNA interaction. It is noteworthy that IFNgamma decreases TNFalpha-induced histone acetyl transferase (HAT) and increases histone deacetylase (HDAC) activities. Finally, trichostatin A, an HDAC inhibitor, prevents IFNgamma inhibitory action on TNFalpha-induced gene expression. Together, our data indicate that IFNgamma is a potent inhibitor of specific TNFalpha-inducible inflammatory genes by acting on NF-kappaB transactivation via the modulation of HDAC function.
DOI Link: 10.1124/mol.106.030171
ISSN: 0026-895X
Links: http://hdl.handle.net/2381/15174
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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