Interferon alpha/beta promotes cell survival by activating nuclear factor kappa B through phosphatidylinositol 3-kinase and Akt

Interferons (IFNs) play critical roles in host defense by modulating gene e xpression via activation of signal transducer and activator of transcriptio n (STAT) factors. IFN-alpha/beta also activates another transcription facto r, nuclear factor kappaB (NF-kappaB), which protects cells against apoptoti c stimuli. NF-kappaB activation requires the IFN-dependent association of S TAT3 with the IFNAR1 chain of the IFN receptor. IFN-dependent NF-kappaB act ivation involves the sequential activation of a serine kinase cascade invol ving phosphatidylinositol 3-kinase (PI-3K) and Akt. Whereas constitutively active PI-3K and Akt induce NF-kappaB activation, Ly294002 (a PI-3K inhibit or), dominant-negative PI-3K, and kinase-dead Akt block IFN-dependent NF-ka ppaB activation. Moreover, dominant-negative PI-3K blocks IFN-promoted degr adation of kappa Box alpha. Ly294002, a dominant-negative PI-3K construct, and kinase-dead Akt block IFN-promoted cell survival, enhancing apoptotic c ell death. Therefore, STAT3, PI-3K, and Akt are components of an IFN signal ing pathway that promotes cell survival through NF-kappaB activation.