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Interferons (IFNs) induce transcription of major histocompatibility complex (MHC) class I genes through the conserved IFN consensus sequence (ICS) that contains an IFN response motif shared by many IFN-regulated genes. By screening mouse AZAP expression libraries with the ICS as a probe, we isolated a cDNA clone encoding a protein that binds the ICS, designated ICSBP. Protein blot analysis with labeled oligonucleotide probes showed that ICSBP binds not only the MHC class I ICS but also IFN response motifs of many IFN-regulated genes, as well as a virus-inducible element of the IFN-,f gene. The ICSBP cDNA encodes 424 amino acids and a long 3' untranslated sequence. The N-terminal 115 amino acids correspond to a putative DNA-binding domain and show significant sequence similarity with other cloned IFN response factors (IRF-1 and IRF-2). Because of the structural similarity and shared binding specificity, we conclude that ICSBP is a third member of the IRF gene family, presumably playing a role in IFN-and virus-mediated regulation of many genes. Although IRF-1 and IRF-2 share some similarity in their C-terminal regions, ICSBP shows no similarity to IRF-1 or IRF-2 in this region, suggesting that it is more distantly related. We show that ICSBP mRNA is expressed predominantly in lymphoid tissues and is inducible preferentially by IFN-y. The induction by IFN-y appears to be predominant in lymphocytes and macrophages, implying that ICSBP plays a regulatory role in cells of the immune system. The presence of multiple factors that bind common IfN response motifs may partly account for the complexity and diversity of IFN action as well as IFNregulated gene expression.Interferons (IFNs) are potent biomodulators (1, 2). They regulate many cellular genes involved in defense against viral and bacterial infection, enhance immune responses, and control cell growth. We have been interested in IFNmediated induction of major histocompatibility complex (MHC) class I genes. We and others have observed that a highly conserved upstream cis element, the interferon consensus sequence (ICS), is responsible for IFN-mediated induction of MHC class I genes (3-6). Several nuclear factors that bind to the ICS are either constitutively expressed or induced by IFN treatment (3, 7). A number of groups (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) have shown that other IFN-regulated genes have IFN response motifs that are very similar to part of the ICS and to each other. These elements are essential for virus-or IFNinduced transcription of the corresponding genes and bind to the same or very similar factors. These reports put forward the notion that IFN genes and IFN-regulated genes are controlled by shared cis motifs that bind shared transcription factors. We

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