Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection

Khuong B Nguyen, Wendy T Watford, Rachelle Salomon, Sigrun R Hofmann, Gary C Pien, Akio Morinobu, Massimo Gadina, John J O'Shea, Christine A Biron
Science 2002 September 20, 297 (5589): 2063-6
Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-alpha and IFN-beta (IFN-alpha/beta) have been established, their immunoregulatory functions, especially their ability to regulate IFN-gamma production, are poorly understood. Here we show that IFN-alpha/beta activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-gamma production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-alpha/beta induction of IFN-gamma. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.

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