Journal of Biological Chemistry
Volume 281, Issue 17, 28 April 2006, Pages 11678-11684
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Mechanisms of Signal Transduction
NFκB Negatively Regulates Interferon-induced Gene Expression and Anti-influenza Activity*

https://doi.org/10.1074/jbc.M513286200Get rights and content
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Interferons (IFNs) are antiviral cytokines that selectively regulate gene expression through several signaling pathways including nuclear factor κB(NFκB). To investigate the specific role of NFκB in IFN signaling, we performed gene expression profiling after IFN treatment of embryonic fibroblasts derived from normal mice or mice with targeted deletion of NFκB p50 and p65 genes. Interestingly, several antiviral and immunomodulatory genes were induced higher by IFN in NFκB knock-out cells. Chromatin immunoprecipitation experiments demonstrated that NFκB was basally bound to the promoters of these genes, while IFN treatment resulted in the recruitment of STAT1 and STAT2 to these promoters. However, in NFκB knock-out cells IFN induced STAT binding as well as the binding of the IFN regulatory factor-1 (IRF1) to the IFN-stimulated gene (ISG) promoters. IRF1 binding closely correlated with enhanced gene induction. Moreover, NFκB suppressed both antiviral and immunomodulatory actions of IFN against influenza virus. Our results identify a novel negative regulatory role of NFκB in IFN-induced gene expression and biological activities and suggest that modulating NFκB activity may provide a new avenue for enhancing the therapeutic effectiveness of IFN.

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*

This work was supported by National Institutes of Health Grant CA73753 (to L. M. P.) and by funds from the Muirhead Chair Endowment at the University of Tennessee Health Science Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.