NFκB activation is required for interferon regulatory factor-1-mediated interferon β induction

Abstract

The interferon regulatory factor 1 (IRF-1) acts as a transcriptional inducer of the interferon β (IFN-β) gene and interferon-stimulated genes. Here we report that IRF-1-mediated IFN-β induction depends on NFκB activity. IRF-1 by itself initiates NFκB activation by inducing a reduction in cellular MAD3/IκBα, an inhibitor of NFκB. After nuclear translocation, NFκB synergizes with IRF-1 on the cis-elements positive regulatory domain (PRD)II and PRDI/III to induce transcription of the IFN-β gene. In contrast with IFN-β transcription induced by dsRNA or virus, c-Jun/ATF-2 binding to PRDIV is not involved. Recombinant MAD3/IκBα is phosphorylated in vitro by extracts from IRF-l-expressing cells. IRF-1-dependent MAD3/IκBα degradation is not detectable in cells expressing a dominant negative mutant of the protein kinase PKR, suggesting that PKR mediates MAD3/IκBα degradation.