Journal of Biological Chemistry
Volume 274, Issue 8, 19 February 1999, Pages 4801-4806
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CELL BIOLOGY AND METABOLISM
Involvement of Double-stranded RNA-activated Protein Kinase in the Synergistic Activation of Nuclear Factor-κB by Tumor Necrosis Factor-α and γ-Interferon in Preneuronal Cells*

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Tumor necrosis factor-α (TNF-α) and γ-interferon (Ifn-γ) cooperate during a variety of biological responses and ultimately synergistically enhance the expression of genes involved in immune and inflammatory responses. Recently, we demonstrated that Ifn-γ can significantly potentiate TNF-α-induced nuclear factor (NF)-κB nuclear translocation in neuronal derived and endothelial cell lines. The mechanism by which these two cytokines exert their synergistic effect on NF-κB involves the de novo degradation of the NF-κB inhibitor, IκBβ. The double-stranded RNA-dependent kinase PKR is Ifn-inducible and has been implicated in the activation of NF-κB; therefore, we examined the possibility that PKR may play a role in the synergistic activation of NF-κB during TNF-α/Ifn-γ cotreatment. The PKR inhibitor 2-aminopurine (2-AP) inhibited TNF-α/Ifn-γ-induced NF-κB nuclear translocation in neuronal derived cells but not in endothelial cells. The induced degradation of IκBβ, which is normally observed upon TNF-α/Ifn-γ cotreatment, was blocked completely by 2-AP in neuronal derived cells. Also, 2-AP treatment or overexpression of a catalytically inactive PKR inhibited the TNF-α/Ifn-γ-induced synergistic activation of κB-dependent gene expression. Our results suggest that the signal generated by Ifn-γ during TNF-α/Ifn-γ cotreatment may require PKR to elicit enhanced NF-κB activity, and this signal may affect the stability of the IκBβ protein.

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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Supported by National Institutes of Health/National Research Service Award Fellowship 1 F32 AG05745. Present address: Bayer Corp., R&D Pathogen Safety Research, Research Triangle Park, NC 27709.

Supported by National Institutes of Health Grant AI34039.