The role of STAT3 inhibitors in Type I IFN-mediated signaling and antiviral responses
Date Issued
2012
Date
2012
Author(s)
Liao, Chien-Hui
Abstract
Type I interferons (IFNs) plays a key role in innate immunity to protect host from viral and bacterial infections. Signal transducer and activator of transcription (STAT) proteins, such as STAT1, STAT2, and STAT3, are activated by IFN-α/β. Unlike the complex of STAT1 and STAT2, which promotes type I IFN-mediated antiviral response, STAT3 negatively regulates type I IFN-mediated pathway. In previous study, STAT3 knockout mouse fibroblast (MEFs) and primary bone-marrow-derived macrophages (BMMs) showed enhanced IFN functions. We hypothesize that targeting STAT3 function would enhance IFN-mediated antiviral response. Therefore, we screened different STAT3 inhibitors and investigated their roles in IFN-mediated signaling and functions. Among them, WP1066 was shown to induce higher expression of antivirus-associated genes in both WT MEFs and BMMs in response to IFN-α4 stimulation. Interestingly, the phenomenon was abolished in the absence of STAT3, suggesting that the effect of the inhibitor was STAT3-dependent. The effect of WP1066 in IFN-α4-mediated antiviral response was further examined by infecting MEFs with encephalomyocarditis virus (EMCV). Enhanced antiviral response was revealed by reduced expression of EMCV-specific gene in infected cells in a dose-dependent manner. In addition, the suppressive effect of FL- and N-terminal domain- (NTD) STAT3 in STAT3KO MEFs in response to type I IFN was reversed by WP1066 treatment. We further addressed the mechanism of WP1066 activity and found that the inhibitor did not affect phosphorylation and nuclear translation of STAT1 and STAT2. Taken together, these results suggest that WP1066 may enhance antiviral function of cells by targeting STAT3 function. This study provides a therapeutic approach for virus infection by targeting STAT3 to enhance type I IFN-induced antiviral response.
Subjects
STAT3
inhibitor
interferon
Type
thesis
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