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.
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.
Keslacy
Stefan
S
Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, University of Pennsylvania School of Medicine, Translational Research Laboratories Building, Philadelphia PA 19104-3403, USA.
Tliba
Omar
O
Baidouri
Hasna
H
Amrani
Yassine
Y
D002478:Cells, Cultured; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D016328:NF-kappa B / Q000235:genetics*; D014132:Trachea / Q000166:cytology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006655:Histone Deacetylases