Lack of Essential Role of NF-κB p50, RelA, and cRel Subunits in Virus-Induced Type 1 IFN Expression

Abstract

Type 1 IFNs (IFN-alphabeta) play pivotal roles in the host antiviral response and in TLR-induced signaling. IFN regulatory factor (IRF) and NF-kappaB transcription factors are thought to be crucial for virus-induced mRNA expression of IFN-beta. Although recent studies have demonstrated essential roles for IRF3 and IRF7, the definitive role of NF-kappaB factors in IFN-beta (or IFN-alpha) expression remains unknown. Using mice deficient in distinct members of the NF-kappaB family, we investigated NF-kappaB function in regulating type 1 IFN expression in response to Sendai virus and Newcastle disease virus infection. Surprisingly, IFN-beta and IFN-alpha expression was strongly induced following virus infection of mouse embryonic fibroblasts (MEFs) from p50(-/-), RelA/p65(-/-), cRel(-/-), p50(-/-)cRel(-/-), and p50(-/-)RelA(-/-) mice. Compared with wild-type MEFs, only RelA(-/-) and p50(-/-)RelA(-/-) MEFs showed a modest reduction in IFN-beta expression. To overcome functional redundancy between different NF-kappaB subunits, we expressed a dominant-negative IkappaBalpha protein in p50(-/-)RelA(-/-) MEFs to inhibit activation of remaining NF-kappaB subunits. Although viral infection of these cells failed to induce detectable NF-kappaB activity, both Sendai virus and Newcastle disease virus infection led to robust IFN-beta expression. Virus infection of dendritic cells or TLR9-ligand CpG-D19 treatment of plasmacytoid dendritic cells from RelA(-/-) or p50(-/-)cRel(-/-) mice also induced robust type 1 IFN expression. Our findings therefore indicate that NF-kappaB subunits p50, RelA, and cRel play a relatively minor role in virus-induced type 1 IFN expression.