title: STAT4-mediated transcriptional repression of the IL5 gene in human memory Th2 cells.
abstract: Type I interferon (IFN-α/β) plays a critical role in suppressing viral replication by driving the transcription of hundreds of interferon-sensitive genes (ISGs). While many ISGs are transcriptionally activated by the ISGF3 complex, the significance of other signaling intermediates in IFN-α/β-mediated gene regulation remains elusive, particularly in rare cases of gene silencing. In human Th2 cells, IFN-α/β signaling suppressed IL5 and IL13 mRNA expression during recall responses to T-cell receptor (TCR) activation. This suppression occurred through a rapid reduction in the rate of nascent transcription, independent of de novo expression of ISGs. Further, IFN-α/β-mediated STAT4 activation was required for repressing the human IL5 gene, and disrupting STAT4 dimerization reversed this effect. This is the first demonstration of STAT4 acting as a transcriptional repressor in response to IFN-α/β signaling and highlights the unique activity of this cytokine to acutely block the expression of an inflammatory cytokine in human T cells.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Gonzales-van Horn
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Leonardo D
authors.initials: LD
authors.lastname: Estrada
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Nicolai S C
authors.initials: NS
authors.lastname: van Oers
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Farrar
mesh_terms: D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D016898:Interferon-alpha; D018793:Interleukin-13; D015848:Interleukin-5; D050797:STAT4 Transcription Factor; D016899:Interferon-beta
keywords: CD4 T cells; Cytokines; Gene regulation; IFNs; Transcription factors