WEI-BEI WANGHao-Kang DenDavid E. LevyCHIEN-KUO LEE2018-09-102018-09-102010-10http://scholars.lib.ntu.edu.tw/handle/123456789/357709Special Issue – Abstracts and ReviewsChicago, IL USAType I interferons (IFNs) are crucial cytokines for innate immunity to combat viral and bacterial infections. Signaling by type I IFN receptors triggers the activation of signal transducers and activators of transcription (STAT) proteins, including STAT1, STAT2, and STAT3. While an essential role of STAT1 and STAT2 for type I IFN-induced antiviral responses has been well documented by the studies of gene-targeted mice and human mutations, the role of STAT3 for this response remains unclear. Using MEFs or bone marrow-derived macrophages (BMMs) lacking STAT3, we demonstrate that STAT3 negatively regulates type I IFN-mediated responses. Enhanced signaling, gene induction and antiviral response were observed in STAT3KO cells in response to IFNα/β. Restoration of STAT3 to STAT3KO MEFs inhibited the otherwise enhanced responses, suggesting that the altered phenotypes seen in STAT3KO cells were intrinsic to the loss of STAT3. One mechanism for the enhanced antiviral response in the absence of STAT3 might operate through a positive feedback loop of IFN production and signaling in a MDA5-dependent manner. In addition, STAT3 also appeared to directly suppress IFN response in a manner dependent on its N-terminal domain and independent of its function as a transcription factor. In ChIP assay, STAT3 also inhibited the recruitment of IFN-activated transcriptional complexes to their promoters. The suppressive effect of STAT3 in antiviral responses seemed to be a general phenomenon, as R848, a ligand of TLR7 mimicking viral infection, also stimulated an enhanced response in STAT3KO BMMs and mice. Taken together, these results define STAT3 as a negative regulator of type I IFN-mediated signaling and functions and may provide a therapeutic target for viral infections.enconference paper10.1016/j.cyto.2010.07.275