IFNα/β promotes cell survival by activating NF-κB

IFNs play critical roles in host defense by modulating the expression of various genes via signal transducer and activator of transcription factors. We show that IFN alpha/beta activates another important transcription factor, NF-kappaB. DNA-binding activity of NF-kappaB was induced by multiple type 1 IFNs and was promoted by IFN in a diverse group of human, monkey, rat, and murine cells. Human IFN promoted NF-kappaB activation in murine cells that express the human IFN alpha/beta receptor-1 signal-transducing chain of the type 1 IFN receptor. IFN promotes inhibitor of kappa B alpha (I kappaB alpha) serine phosphorylation and degradation, and stimulates NF-kappaB DNA-binding and transcriptional activity. Importantly, IFN promotes cell survival by protecting cells against a variety of proapoptotic stimuli, such as virus infection and antibody-mediated crosslinking. Expression of superrepressor forms of I kappaB alpha, besides inhibiting IFN-mediated NF-kappaB activation and I kappaB alpha degradation, also enhanced apoptotic cell death in IFN-treated cells. We conclude that NF-kappaB activation by IFN alpha/beta is integrated into a signaling pathway through the IFN alpha receptor-1 chain of the type 1 IFN receptor that promotes cell survival in apposition to various apoptotic stimuli.