IFNs play critical roles in host defense by modulating the expression of va
rious genes via signal transducer and activator of transcription factors. W
e 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, a
nd murine cells. Human IFN promoted NF-kappaB activation in murine cells th
at 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 survi
val by protecting cells against a variety of proapoptotic stimuli, such as
virus infection and antibody-mediated crosslinking. Expression of superrepr
essor forms of I kappaB alpha, besides inhibiting IFN-mediated NF-kappaB ac
tivation and I kappaB alpha degradation, also enhanced apoptotic cell death
in IFN-treated cells. We conclude that NF-kappaB activation by IFN alpha/b
eta 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.