NF kappa B activation is required for interferon regulatory factor-1-mediated interferon beta induction

The interferon regulatory factor 1 (IRF-1) acts as a transcriptional induce r of the interferon beta (IFN-beta) gene and interferon-stimulated genes. H ere we report that IRF-1-mediated IFN-beta induction depends on NF kappa B activity. IRF-1 by itself initiates NF kappa B activation by inducing a red uction in cellular MAD3/I kappa B alpha, an inhibitor of NF kappa B. After nuclear translocation, NF kappa B synergizes with IRF-1 on the cis-elements positive regulatory domain (PRD)II and PRDI/III to induce transcription of the IFN-beta gene. In contrast with IFN-beta transcription induced by dsRN A or virus, c-Jun/ATF- 2 binding to PRDIV is not involved. Recombinant MAD3 /I kappa B alpha is phosphorylated in vitro, by extracts from IRF-1-express ing cells. IRF-1-dependent MAD3/I kappa B alpha degradation is not detectab le in cells expressing a dominant negative mutant of the protein kinase PKR , suggesting that PKR mediates MAD3/I kappa B alpha degradation.