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

Interferons (IFNs) are antiviral cytokines that selectively regulate gene expression through several signaling pathways including nuclear factor kappa B (NF kappa B). To investigate the specific role of NF kappa B in IFN signaling, we performed gene expression profiling after IFN treatment of embryonic fibroblasts derived from normal mice or mice with targeted deletion of NF kappa B p50 and p65 genes. Interestingly, several antiviral and immunomodulatory genes were induced higher by IFN in NF kappa B knock-out cells. Chromatin immunoprecipitation experiments demonstrated that NF kappa B 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 NF kappa B 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, NF kappa B suppressed both antiviral and immunomodulatory actions of IFN against influenza virus. Our results identify a novel negative regulatory role of NF kappa B in IFN-induced gene expression and biological activities and suggest that modulating NF kappa B activity may provide a new avenue for enhancing the therapeutic effectiveness of IFN.