RNA-Dependent Protein Kinase PKR Is Required for Activation of NF-κB by IFN-γ in a STAT1-Independent Pathway

The IFN-inducible dsRNA-activated protein kinase PKR regulates protein synthesis through phosphorylation of eukaryotic initiation factor-2alpha. It also acts as a signal transducer for transcription factors NF-kappaB, IFN regulatory factor-1, and activating transcription factor-2. IFN-gamma, a pleiotropic cytokine, elicits gene expression by activating the Janus kinase-STAT signaling pathway. IFN-gamma can synergize with TNF-alpha to activate NF-kappaB in a number of cell lines. Here we show that IFN-gamma alone can activate NF-kappaB, by a Janus kinase-1-mediated, but Stat1-independent, mechanism. NF-kappaB activation by IFN-gamma is associated with degradation of IkappaB beta. The IFN-gamma response can be blocked by 2',5'-oligoadenylate-linked antisense chimeras against PKR mRNA. There was no activation of NF-kappaB by IFN in PKR-null cells, indicating that PKR is required for IFN-gamma signaling to NF-kappaB.