NFκB negatively regulates interferon-induced gene expression and anti-influenza activity

Abstract

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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.