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Type I interferons (IFNs) mediate potent antiviral and antiproliferative activities on target cells through the activation of new genes. Characterization of their ability to induce these genes led to the elucidation of the JAK-STAT signalling pathway, where Janus kinases (JAKs) are receptor-associated tyrosine kinases and signal transducers and activators of transcription (STATs) are the transcription factors they activate.

Type I IFN (e.g., IFN-α/β) signalling entails the rapid receptor-dependent activation of Stat1 and Stat2. Once activated, these two STATs can either heterodimerize, associate with the DNA binding protein IRF-9 (p48) and form ISGF-3 (IFN-stimulated gene factor-3), or they can form Stat1 homodimers. ISGF-3 promotes the activation of genes through the IFN-stimulated response element (ISRE). ISRE-driven genes include Ly-6C, the double-stranded RNA kinase (PKR), 2' to 5' oligoadenylate synthase (OAS), MX and potentially MHC class I. Stat1 homodimers, which also play a critical role in transducing signals for IFN-γ, promote the activation of genes through members of the γ activation site (GAS) family of enhancers. GAS-driven genes including IRF-1, CIITA (an activator MHC class II), IGTP, MIG and IP-10. Consistent with these observations, Stat1 knockout mice are defective in their response to both type I and type II IFNs. Thus, Stat2, an uncharacteristic member of the STAT family, is unique to the biological response to type I IFNs.

Receptor gene targeting studies have provided important insight into the distinct biological responses to type I and II IFNs. Specifically, type I IFN receptor α chain (IFNAR1) null mice are exquisitely sensitive to infection with vesicular stomatitis virus (VSV), semliki forest virus (SFV), vaccinia virus (VV) and lymphocytic choriomeningitis virus (LCMV) but not to intracellular pathogens. In contrast, IFN-γ and IFN-γ receptor null mice are defective in their response to VV and LCMV but not VSV and SFV.

[1] Park, C. et al., Immunity, 13, 795-804 (2000).