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Inhibition of Tumor Necrosis Factor--Inducible Inflammatory Genes by Interferon- Is Associated with Altered Nuclear Factor-B Transactivation and Enhanced Histone Deacetylase Activity

Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

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- (TNF) and interferon- (IFN) or endogenous IFN 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 IFN (1000 U/ml) markedly inhibited TNF-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-B-dependent in that TNF-induced expression of IL-6, IL-8, and eotaxin was dose-dependently inhibited by the selective IKK inhibitor 4-(2'-aminoethyl)amino-1,8-dimethylimidazo[1,2-a]quinoxaline (BMS-345541) (1-30 µM). Using a luciferase reporter construct containing B sites, we found that IFN (10-1000 U/ml) inhibits NF-B-dependent gene transcription in a dose-dependent manner. Moreover, IFN failed to affect TNF-induced IK phosphorylation or IB degradation as well as nuclear NF-B/DNA interaction. It is noteworthy that IFN decreases TNF-induced histone acetyl transferase (HAT) and increases histone deacetylase (HDAC) activities. Finally, trichostatin A, an HDAC inhibitor, prevents IFN inhibitory action on TNF-induced gene expression. Together, our data indicate that IFN is a potent inhibitor of specific TNF-inducible inflammatory genes by acting on NF-B transactivation via the modulation of HDAC function.

Address correspondence to: Dr. Yassine Amrani, Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, University of Pennsylvania School of Medicine, Translational Research Laboratories Building, Suite 1200, 125 South 31st Street, Philadelphia PA 19104-3403. E-mail: amrani{at}mail.med.upenn.edu

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