title: Cooperation among Stat1, glucocorticoid receptor, and PU.1 in transcriptional activation of the high-affinity Fc gamma receptor I in monocytes.
abstract: IFN-gamma and glucocorticoids regulate inflammatory and immune responses through Stat1 and glucocorticoid receptor (GR) transcription factors, respectively. The biological responses to these polypeptides are determined by integration of various signaling pathways in a cell-type and promoter-dependent manner. In this study we have characterized the molecular basis for the functional cooperation between IFN-gamma and dexamethasone (Dex) in the induction of the high-affinity Fc gamma receptor I (Fc gamma RI) in monocytes. Dex did not affect IFN-gamma-induced Stat1 DNA binding activity or induce novel DNA-binding complexes to the Fc gamma RI promoter. By using cell systems lacking functional GR or Stat1, we showed that GR stimulated Stat1-dependent transcription in a ligand-dependent manner, while Stat1 did not influence GR-dependent transcription. The cooperation required phosphorylation of Tyr701, DNA binding, and the trans-activation domain of Stat1, but did not involve Ser727 phosphorylation of Stat1 or physical interaction between GR and Stat1. The costimulatory effect of Dex was not dependent on a consensus glucocorticoid response element in the Stat1-responsive promoters, but required the DNA-binding and trans-activation functions of GR, and Dex-induced protein synthesis. GR activated the natural Fc gamma RI promoter construct, and this response required both Stat1 and the Ets family transcription factor PU.1. Previously, physical association between GR and Stat5 has been shown to enhance Stat5-dependent and suppress GR-dependent transcription. The results shown here demonstrate a distinct, indirect mechanism of cross-modulation between cytokine and steroid receptor signaling that integrates Stat1 and GR pathways with cell type-specific PU.1 transcription factor in the regulation of Fc gamma RI gene transcription.
authors.affiliation: Institute of Medical Technology, and Department of Medical Biochemistry, University of Tampere, Tampere, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Aittomäki
authors.forename: M
authors.initials: M
authors.lastname: Pesu
authors.forename: B
authors.initials: B
authors.lastname: Groner
authors.forename: O A
authors.initials: OA
authors.lastname: Jänne
authors.forename: J J
authors.initials: JJ
authors.lastname: Palvimo
authors.forename: O
authors.initials: O
authors.lastname: Silvennoinen
mesh_terms: D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D008894:Milk Proteins; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology*; D014407:Tumor Cells, Cultured; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D004247:DNA; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D007371:Interferon-gamma; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; D017452:Receptors, IgG; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494079:STAT1 protein, human