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Molecular Pharmacology

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Research ArticleArticle

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

Stefan Keslacy, Omar Tliba, Hasna Baidouri and Yassine Amrani
Molecular Pharmacology February 2007, 71 (2) 609-618; DOI: https://doi.org/10.1124/mol.106.030171
Stefan Keslacy
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Omar Tliba
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Hasna Baidouri
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Yassine Amrani
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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.

Footnotes

  • This work was supported by National Institutes of Health grant HL064063, the University of Pennsylvania Research Foundation, and American Lung Association grant CI-21948-N (to Y.A.).

  • ABBREVIATIONS: TNFα, tumor necrosis factor α; IκB, inhibitor of κB; IκK, Iκ kinase; IFN, interferon; NF-κB, nuclear factor κB; HAT, histone acetyltransferase; HDAC, histone deacetylase; IL, interleukin; ASM, airway smooth muscle; RANTES, regulated upon activation normal T-cell expressed and secreted; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; TSA, trichostatin A; PCR, polymerase chain reaction; SEAP, secreted alkaline phosphatase; r, recombinant; BMS 345541, 4-(2′-aminoethyl)amino-1,8-dimethylimidazo[1,2-a]quinoxaline.

    • Received August 24, 2006.
    • Accepted November 15, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (2)
Molecular Pharmacology
Vol. 71, Issue 2
1 Feb 2007
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Research ArticleArticle

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

Stefan Keslacy, Omar Tliba, Hasna Baidouri and Yassine Amrani
Molecular Pharmacology February 1, 2007, 71 (2) 609-618; DOI: https://doi.org/10.1124/mol.106.030171

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Research ArticleArticle

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

Stefan Keslacy, Omar Tliba, Hasna Baidouri and Yassine Amrani
Molecular Pharmacology February 1, 2007, 71 (2) 609-618; DOI: https://doi.org/10.1124/mol.106.030171
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