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First published on November 15, 2006; DOI: 10.1124/mol.106.030171

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Received for publication August 25, 2006.
Revised November 15, 2006.
Accepted for publication November 15, 2006.

INHIBITION OF TNF{alpha}-INDUCIBLE INFLAMMATORY GENES BY IFN{gamma} IS ASSOCIATED WITH ALTERED NF-{kappa}B TRANSACTIVATION AND ENHANCED HDAC ACTIVITY

Stefan Keslacy 1, Omar Tliba 1, Hasna Baidouri 1, Yassine Amrani 1*

1 Univ. of Pennsylvania Medical Center

* Address correspondence to: E-mail: amrani{at}mail.med.upenn.edu

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 TNF{alpha} and Interferon (IFN){gamma} or endogenous IFN{beta} results in a synergistic induction of various pro-inflammatory genes (including CD38 and RANTES) in ASM cells. In contrast to these studies, we found that IFN{gamma}(1000 U/ml) markedly inhibits TNF{alpha}-induced expression of 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-{kappa}B-dependent as TNF{alpha}-induced expression of IL-6, IL-8 and eotaxin was dose-dependently inhibited by the selective IKK{beta} inhibitor (BMS-345541, 1-30 µM). Using a luciferase reporter construct containing {kappa}B sites, we found that IFN{gamma} (10-1000 U/ml) inhibits NF-{kappa}B-dependent gene transcription in a dose-dependent manner. Moreover, IFN{gamma} failed to affect TNF{alpha}-induced IKK{beta} phosphorylation or I{kappa}B degradation as well as nuclear NF-{kappa}B/DNA interaction. Interestingly, IFN{gamma} decreases TNF{alpha}-induced histone acetyl transferase (HAT) and increases histone deacetylase (HDAC) activities. Finally, Trichostatin A, an HDAC inhibitor, prevents IFN{gamma} inhibitory action on TNF{alpha}-induced gene expression. Together, our data indicate that IFN{gamma} is a potent inhibitor of specific TNF{alpha}-inducible inflammatory genes by acting on NF-{kappa}B-transactivation via the modulation of HDAC function.


Key words: Interferons, Tumor necrosis factor, NFkappaB, Transcriptional coactivators


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