Role of STAT3 in Type I Interferon Responses

Abstract

Type I interferons (IFN / ? ? ) induce antiviral responses and have immunomodulatory effects that can either promote or suppress immunity and inflammation. In myeloid cells IFN ? ? / activates sig- nal transducers and activators of transcription STAT1, STAT2, and STAT3.STAT1andSTAT2mediate the antiviral and inflammatory effects of IFN ? ? / , but the function of IFN / ? ? -activated STAT3 is not known.Weinvestigated the role of STAT3 in type I IFN signal- ing in myeloid cells by modulatingSTAT3expressionandthe inten- sity of STAT3 activation using overexpression and RNA interfer- ence and determining the effectsondownstream signaling and gene expression. IFN ? -activated STAT3 inhibited STAT1-dependent gene activation, thereby down-regulating IFN -mediated in- ? duction of inflammatory mediators such as the chemokines CXCL9 (Mig) and CXCL10 (IP-10). At the same time, IFN ? -activated STAT3 supported ISGF-3-dependent induction of antiviral genes. STAT3 did not suppress STAT1 tyrosine phosphorylation or nuclear translocation but instead sequestered STAT1 and sup- pressed the formation of DNA-bindingSTAT1homodimers. These results identify a regulatory function for STAT3 in attenuating the inflammatory properties of type I IFNs and provide amecha- nism of suppression of STAT1 function that differs from previously described suppression of tyrosine phosphorylation.Theresults sug- gest that changes in the relative expression and activation ofSTAT1 and STAT3 that occur during immune responses determine the nature of cellular responses to type I IFNs.