REGULATION OF TYPE-I INTERFERON GENE-EXPRESSION BY INTERFERON REGULATORY FACTOR-III

The genes of the family of interferon (IFN) regulatory factors (IRF) e ncode DNA binding transcriptional factors that are involved in modulat ion of transcription of IFN and interferon-induced genes (ISG), The pr esence of IRF binding sites in the promoter region of IFNA and IFNB ge nes indicates that IRF factors recognizing these sites play an importa nt role in the virus-mediated induction of these genes, We have descri bed a novel human gene of this family, IRF-3, that is constitutively e xpressed in a variety of cell types, IRF-3 binds to the interferon-sen sitive response element (ISRE) present in the ISG15 gene promoter and activates its transcriptional activity, In the present study, we exami ned whether IRF-3 can modulate transcriptional activity of IFNA and IF NB promoter regions, Our results demonstrate that IRF-3 can bind to th e IRF-like binding sites present in the virus-inducible region of the IFNA4 promoter and to the PRDIII region of the IFNB promoter but canno t alone stimulate their transcriptional activity in the human cell lin e, 293, However, the fusion protein generated from the IRF-3 binding d omain and the RelA(p65) activation domain effectively activates both I FNA4 and IFNB promoters. Cotransfection of IRF-3 and RelA(p65) express ion plasmids activates the IFNB gene promoter but not the promoter of IFNA4 gene that does not contain the NF-kB binding site. Surprisingly, activation of the IFNA4 gene promoter by virus and IRF-1 in these cel ls was inhibited by IRF-3, These data indicate that in 293 cells IRF-3 does not stimulate expression of IFN genes but can cooperate with Rel A(p65) to stimulate the IFNB promoter.