Essential and non-redundant roles of p48 (ISGF3γ) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies

Background: Interferons (IFNs) are a class of cytokines which confer cellular resistance against viral infections. Type I (IFN-α and -β) and type II (IFN-γ) IFNs utilize distinct receptors, the stimulation of which results in the induction of down-stream target genes. These target genes usually contain within their promoter region an IFN responsive element, termed ISRE (IFN stimulated response element) which binds a heterotrimeric transcription factor, ISGF3 (IFN-stimulated gene factor 3) consisting of p48 (ISGF3 γ), Stat1 (Signal transducers and activators of transcription-1; α or β), and Stat2. The ISRE sequence overlaps with that of IRF-E which binds another IFN-inducible factor, IRF-1 (IFN regulatory factor-1). Results: We generated mice lacking p48 by gene targeting. We show that p48 plays an essential role in both type I and type II IFN responses; activation of IFN-inducible genes and establishment of the antiviral state by IFN-α or -γ are both severely impaired, and ISRE-binding activities induced by both IFNs are absent in the p48-negative embryonic fibroblasts (EFs). Furthermore, we generated mice deficient for both p48 and IRF-1 and found that at least one IFN-inducible gene is dependent on both factors. Conclusions: p48 and IRF-1 do not perform redundant functions in the cell, but rather complement one another in both type I and II IFN responses.