IFN-Mediated Antiviral Response STAT3 Negatively Regulates Type I

Type I IFNs are crucial cytokines of innate immunity for combating viral infections. Signaling through type I IFN receptors triggers the activation of STAT proteins, including STAT1, STAT2, and STAT3. Although an essential role of STAT1 and STAT2 for type I IFN-induced antiviral response has been well established by studies of gene-targeted mice and human mutations, the role of STAT3 for this response remains unclear. Using gain-of-function and loss-of-function approaches, we demonstrated that STAT3 negatively regulates type I IFN-mediated response. STAT3 knockdown or knockout cells displayed enhanced gene expression and antiviral activity in response to IFN-a/b. Restoration of STAT3 to STAT3KO cells resulted in attenuation of the response. Upon viral infection, increased type I IFN production in STAT3KO cells resulted in enhanced STAT activation and ISG expression. One mechanism for the enhanced IFN production and response in the absence of STAT3 might operate through an MDA5-dependent manner. STAT3 also appeared to suppress IFN response directly in a manner dependent on its N-terminal domain and independent of its function as a transcriptional factor. Taken together, these results define STAT3 as a negative regulator of type I IFN response and provide a therapeutic target for viral infections. T ype I IFNs, composed of an IFN-b and several IFN-a species, are critical cytokines of innate immunity for triggering antiviral response. Antiviral functions of type I IFNs are mediated by induction of IFN-stimulated genes (ISGs), including protein kinase R (PKR), 29,59-oligoadenylate synthetase (OAS), RNase L, inducible NO synthase (iNOS), and IFN regulatory factors (IRFs), which interfere with virus replication or trigger cell apoptosis to avoid viral spread (1). The signaling pathways resulting in induction of the ISGs involve activation of STAT family members, including STAT1, STAT2, and STAT3, by tyrosine and serine phosphorylation (2). Activated STAT1, STAT2, and IRF9 form the ISGF3 complex, binding to the IFN-stimulated response element (ISRE) in the promoters of ISGs (3). Activated STAT1 and STAT3 form a homodimer, or heterodimer, and bind to IFN-g–activated site. Whereas the homodimer of STAT1 or STAT3 and the heterodimer of STAT1-STAT3 can bind to similar cognate sites in vitro, the in vivo binding sites for these dimers are most likely to be different because the downstream targets of STAT1 and STAT3 and the phenotypes of STAT1-and STAT3-deficient mice are quite distinct (4–7). STAT3 is a signaling mediator of IL-6 and IL-10 family members and other cytokines such as leptin and G-CSF (6, 8). …