The role of NF-kappaB in Type I interferon regulated gene expression and biological actions

Type I interferons (IFNs) are a family of multifunctional cytokines that block viral infection, inhibit cell proliferation, and modulate cell differentiation through activating the well known JAK-STAT pathway, as well as NF-kappaB pathway. The purpose of the current study was to characterize the role of NF-kappaB in IFN signaling and biological actions.; To investigate the specific role of NF-kappaB in interferon signaling, we performed gene expression profiling after IFN treatments of MEFs derived from mice with targeted deletion in NF-kappaB p50 and p65 genes. A subset of genes involved in antiviral and immunomodulatory activities such as Ifi47, Tap1, and Mx1, were induced higher by IFN in NF-kappaB knockout cells compared to wild type cells. Chromatin Immunoprecipitation (ChIP) experiments demonstrated that binding of p50-p50 or p65-p50 NF-kappaB dimers to the promoter of these genes occurred prior to the binding of Irf1 transcription factor, suggesting that IFN induction of these genes is suppressed through NF-kappaB. These results revealed the crosstalk between JAK-STAT pathway and NF-kappaB pathway.; To characterize the role of NF-kappaB in the cellular responses to Type I IFN, we investigated antiviral and immunomodulatory actions of IFN-beta in context of influenza A virus, and anti-proliferative activities of IFN-beta in wild-type MEFs and NF-kappaB p50 and p65 knockout MEFs. We showed that deletion of NF-kappaB activity sensitized MEFs to antiviral effects of IFN against intracellular influenza A PR8 virus. In addition, NF-kappaB knockout cells displayed higher induction of cell surface MHC class I molecules by IFN and antigen presentation following the influenza virus infection. However, the antiproliferative action of IFNs was not found to be significantly affected by NF-kappaB. These results indicated that NF-kappaB suppresses antiviral and immunomodulatory actions of IFNs, possibly by selectively regulating a subset of ISGs.; Type I IFNs have been used to treat certain cancers and viral infections for many years, while NF-kappaB inhibitors have also been used to treat diseases such as cancers and autoimmune diseases recently. Our discovery that NF-kappaB suppresses the biological actions of IFN indicates that the combination of IFN and NF-kappaB inhibitors may be used to maximize therapeutic benefits in the treatment of human diseases, while minimizing the undesirable side effects of these agents.