Induction of the interferon (IFN)-alpha/beta gene transcription in virus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-alpha/beta gene expression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered. Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested. In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinct roles of thetwo factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response.

The interferon regulatory factor (IRF) family of transcription factors regulate the interferon (IFN) system, among which IRF-3 is involved in the virus-induced IFN-L L gene expression. Here we show that another member IRF-7 is critical for the IFN-K K gene induction. Unlike the IRF-3 gene, the IRF-7 gene is induced by IFNs through activation of the ISGF3 transcription factor, and IRF-7 undergoes virus-induced nuclear translocation. In cells lacking p48, an essential component of IFN stimulated gene factor 3 (ISGF3), ectopic expression of IRF-7 but not IRF-3 can rescue the deficiency to induce IFN-K K genes. These results indicate that IRF-7 is a key factor in the positive feedback regulation of IFN-K K/L L production.z 1998 Federation of European Biochemical Societies.

The IFN-L L promoter is controlled primarily by the virus-inducible enhancer elements, the IRF-Es. Here we show that IRF-3, an IRF family transcription factor, translocates to the nucleus from the cytoplasm upon virus infection in NIH/3T3 cells. The nuclear IRF-3 is phosphorylated, interacts with the co-activators CBP/ p300, and binds specifically to the IFN-L L IRF-E. Furthermore, overexpression of IRF-3 causes a marked increase in virusinduced IFN-L L mRNA expression. Thus, IRF-3 is a candidate transcription factor mediating the activation of the IFN-L L gene.z 1998 Federation of European Biochemical Societies.

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