STAT3 is a negative regulator of type I IFN-induced antiviral responses

Type I interferons (IFNs) are potent cytokines for innate immunity to combat viral or bacterial infections. It has been well documented that signal transducer and activator of transcription (STAT) proteins, such as STAT1, STAT2, and STAT3, are activated upon IFN-α/β stimulation. While essential roles of STAT1 and STAT2 in IFN-α/β-mediated antiviral responses are demonstrated in gene-targeting mice, the role of STAT3 remains unclear. Using STAT3KO mouse fibroblasts (MEFs) and primary bone-marrow-derived macrophages (BMMs) lacking STAT3, we demonstrated that IFN-α signals in STAT3KO MEFs or BMMs were enhanced. Both microarray and RT-QPCR analysis revealed that induction of several IFN-α-inducible antiviral -associated genes, such as Pkr, Oas, Rnasl, Irf1, and Irf7, is higher in STAT3KO cells than that in wild-type cells in response to IFN-α. Moreover, we also showed that STAT3KO cells also displayed increased antiviral responses to Encephalomyocarditis virus (EMCV) or Vesicular stomatitis virus (VSV) infections with survival levels and decreased viral titers. The enhanced IFN-β and antiviral responses were inhibited in STAT3-restored mutant MEFs, suggesting that STAT3 might negatively regulate these two responses. Interestingly, activation of both STAT1 and STAT2 was enhanced in STAT3KO cells. We also found that the level of IFN-β were increased in STAT3KO cells upon EMCV infection or TLR-ligand stimulation. Therefore, at least, two mechanisms might contribute to the enhanced antiviral activity, namely enhanced signaling of STAT1 and STAT2 and increased IFN-β production in the absence of STAT3. Taken together, these results suggest an important and yet previously uncharacterized role of STAT3 in IFN-α-mediated antiviral responses.