Abstract
Type I interferon (IFN-I) is induced during innate immune response and is required for initiating antiviral activity, growth inhibition, and immunomodulation. STAT1, STAT2, and STAT3 are activated in response to IFN-I stimulation. STAT1, STAT2, and IRF9 form ISGF3 complex which transactivates downstream IFN-stimulated genes and mediates antiviral response. However, the role of STAT3 remains to be characterized. Here, we review the multiple actions of STAT3 on suppressing IFN-I responses, including blocking IFN-I signaling, downregulating the expression of ISGF3 components, and antagonizing the transcriptional activity of ISGF3. Finally, we discuss the evolution of the suppressive activity of STAT3 and the therapeutic potential of STAT3 inhibitors in host defense against viral infections and IFN-I-associated diseases.
Highlights
Frontiers in ImmunologyFine-Tuning of Type I Interferon Response by STAT3. STAT3 was originally identified as acute-phase response factor (APRF) that is activated by IL-6 and binds to the promoters of acute-phase protein genes in hepatocytes to regulate inflammatory responses [1,2,3,4]
Reviewed by: Ana Maria Gamero, Temple University, United States Markus Johannes Hofer, University of Sydney, Australia
STAT3 was originally identified as acute-phase response factor (APRF) that is activated by IL-6 and binds to the promoters of acute-phase protein genes in hepatocytes to regulate inflammatory responses [1,2,3,4]
Summary
Fine-Tuning of Type I Interferon Response by STAT3. STAT3 was originally identified as acute-phase response factor (APRF) that is activated by IL-6 and binds to the promoters of acute-phase protein genes in hepatocytes to regulate inflammatory responses [1,2,3,4]. STAT2 can serve as an adaptor to bridge the interaction between USP18 and IFNAR2, which inhibits ligand binding to the receptor, resulting in decreased receptor dimerization and signaling [42] These results suggest an emerging role of IFNI signaling mediators in negative feedback regulation of IFNI response. Gain- and loss-of-function analyses suggest that STAT3 negatively regulates IFN-α-induced ISG expression and antiviral activity [60]. STAT3 can induce a suppressor to attenuate IFN-I signaling or a miRNA to reduce the expression of ISGF3 components to indirectly block IFN-I response These mechanisms will be elaborated further . Overexpression of IFN-α-activated STAT3 inhibits STAT1dependent gene expression, thereby downregulating the induction of proinflammatory cytokines, including CXCL9 and CXCL10 and a transcription factor IRF1, probably by sequestering activated STAT1 into STAT1:STAT3 heterodimers and reducing DNA binding of STAT1:STAT1 homodimers [57]. IFN-I signaling can be antagonized by STAT3, at least, in two ways: to compete for STAT1 association and for DNA binding (Figure 1A)
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