RNA-dependent protein kinase PKR is required for activation of NF-kappa B by IFN-gamma in a STAT1-independent pathway

The IFN-inducible dsRNA-activated protein kinase PKR regulates protein synt hesis through phosphorylation of eukaryotic initiation factor-2 alpha. It a lso acts as a signal transducer for transcription factors NF-kappaB, IFN re gulatory factor-1, and activating transcription factor-2. IFN-gamma, a plei otropic cytokine, elicits gene expression by activating the Janus kinase-ST AT 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 ac tivate NF-kappaB, by a Janus kinase-1-mediated, but Stat1-independent, mech anism. NF-kappaB activation by IFN-gamma is associated with degradation kap pa of IKB beta. The IFN-gamma response can be blocked by 2',5'-oligoadenyla te-linked antisense chimeras against PKR mRNA. There was no activation of N F-kappaB by IFN in PKR-null cells, indicating that PKR is required for IFN- gamma signaling to NF-kappaB.