Role of STAT3 in Antiviral Responses
Date Issued
2011
Date
2011
Author(s)
Wang, Wei-Bei
Abstract
Type I interferons (IFNs) are potent cytokines for innate immunity to combat viral 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 type I IFN-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 the induction of several IFN-a-inducible antiviral-associated genes was higher in STAT3KO cells than that in wild-type cells in response to IFN-α. Moreover, STAT3KO cells also displayed increased antiviral responses to encephalomyocarditis virus (EMCV) or vesicular stomatitis virus (VSV) infections with increased survival levels and decreased viral titers. STAT3 restoration to STAT3KO MEFs or STAT3 hyper-activation by IL-6 stimulation attenuated the enhanced type I IFN signals and antiviral responses, suggesting that STAT3 negatively regulates these two responses. Surprisingly, STAT3 1-134 a.a. was sufficient to reverse the hyper-antiviral activity. We also found that EMCV infection or TLR agonists stimulation induces the increased level of IFN-α/β in the absence of STAT3 in vitro or in vivo. Additionally, STAT3 might suppress the IFN-β promoter activity upon poly (I:C) treatment and mitochondrial antiviral signaling (MAVS)-mediated signaling pathway. Therefore, at least, two mechanisms might contribute to the enhanced antiviral activity, namely enhanced signaling of type I IFNs and increased IFN-α/β production, in the cells lacking STAT3. Taken together, these results suggest an important and yet previously uncharacterized role of STAT3 in IFN-α/β and TLR-mediated antiviral responses.
Subjects
STAT3
IFN
Antiviral response
Type
thesis
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