Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation.
Type I interferons (IFNalpha/beta) induce antiviral responses and have immunomodulatory effects that can either promote or suppress immunity and inflammation. In myeloid cells IFNalpha/beta activates signal transducers and activators of transcription STAT1, STAT2, and STAT3. STAT1 and STAT2 mediate the antiviral and inflammatory effects of IFNalpha/beta, but the function of IFNalpha/beta-activated STAT3 is not known. We investigated the role of STAT3 in type I IFN signaling in myeloid cells by modulating STAT3 expression and the intensity of STAT3 activation using overexpression and RNA interference and determining the effects on downstream signaling and gene expression. IFNalpha-activated STAT3 inhibited STAT1-dependent gene activation, thereby down-regulating IFNalpha-mediated induction of inflammatory mediators such as the chemokines CXCL9 (Mig) and CXCL10 (IP-10). At the same time, IFNalpha-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 suppressed the formation of DNA-binding STAT1 homodimers. These results identify a regulatory function for STAT3 in attenuating the inflammatory properties of type I IFNs and provide a mechanism of suppression of STAT1 function that differs from previously described suppression of tyrosine phosphorylation. The results suggest that changes in the relative expression and activation of STAT1 and STAT3 that occur during immune responses determine the nature of cellular responses to type I IFNs.
Ho
Hao H
HH
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, New York 10021, USA.
Ivashkiv
Lionel B
LB
D045744:Cell Line, Tumor; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism / Q000502:physiology*; D016898:Interferon-alpha / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation
C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D007370:Interferon Type I; D016898:Interferon-alpha; D050796:STAT3 Transcription Factor