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