Inhibition of tumor necrosis factor-α-inducible inflammatory genes by interferon-γ is associated with altered nuclear factor-κB transactivation and enhanced histone deacetylase activity

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( TNF alpha) and interferon-gamma ( IFN gamma) or endogenous IFN gamma 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 gamma ( 1000 U/ ml) markedly inhibited TNF alpha- 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-kappa B- dependent in that TNF alpha- induced expression of IL- 6, IL- 8, and eotaxin was dose- dependently inhibited by the selective IKK beta inhibitor 4-( 2'-aminoethyl) amino- 1,8- dimethylimidazo[ 1,2- a] quinoxaline ( BMS- 345541) ( 1 - 30 mu M). 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 I kappa K beta phosphorylation or I kappa B degradation as well as nuclear NF-kappa B/ DNA interaction. It is noteworthy that IFN alpha decreases TNF alpha-induced histone acetyl transferase ( HAT) and increases histone deacetylase ( HDAC) activities. Finally, trichostatin A, an HDAC inhibitor, prevents IFN alpha inhibitory action on TNF alpha-induced gene expression. Together, our data indicate that IFN alpha is a potent inhibitor of specific TNF alpha-inducible inflammatory genes by acting on NF-kappa B transactivation via the modulation of HDAC function.