Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signaling and involves histone deacetylase recruitment.
Glucocorticoids are the mainstay of asthma therapy and mediate the repression of a number of cytokine genes, such as Interleukin (IL)-4, -5, -13, and granulocyte macrophage colony-stimulating factor (GM-CSF), which are central to the pathogenesis of asthmatic airway inflammation. The glucocorticoid receptor (GR) mediates repression by a number of diverse ... mechanisms. We have previously suggested that one such repressive activity is by direct binding of GR to elements within the GM-CSF enhancer that are recognized by the nuclear factor of activated T cells.activator protein 1 (NF-AT.AP-1) complex. We reasoned that, because many cytokine genes activated in asthma are transcriptionally regulated by the recruitment of this complex to DNA, their binding sites might provide a target for GR to mediate its repressive effects. Here, we show that transcriptional repression of the Interleukin-5 gene involves recruitment of GR to a DNA region located within the IL-5 proximal promoter, which is bound by NF-AT and AP-1 proteins. GR recruitment had a profound effect upon the activation capacity of GATA3, which has a binding site close to the NF-AT.AP-1 domain in both IL-5 and IL-13 promoters. Repression by GR involves co-repressor recruitment, because treatment of transfected cells with the deacetylase inhibitor trichostatin A caused a partial relief of repression. Additionally, repression could be augmented by co-transfection of cells with a histone deacetylase (HDAC1). These data suggest that the local recruitment of GR causes repression by inhibiting transcriptional activation by GATA3, a key tissue-specific determinant of expression of Th2 cytokines.
Mesh Terms:
Binding Sites, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Nucleus, Cytokines, DNA, DNA, Complementary, DNA-Binding Proteins, Dexamethasone, GATA3 Transcription Factor, Gene Expression Regulation, Glucocorticoids, Granulocyte-Macrophage Colony-Stimulating Factor, Hela Cells, Histone Deacetylases, Humans, Immunoprecipitation, Inflammation, Interleukin-13, Interleukin-5, Jurkat Cells, Models, Genetic, Plasmids, Polymerase Chain Reaction, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, RNA, Receptors, Glucocorticoid, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Trans-Activators, Transcription Factor AP-1, Transcription, Genetic, Transfection
Binding Sites, CD4-Positive T-Lymphocytes, Cell Differentiation, Cell Nucleus, Cytokines, DNA, DNA, Complementary, DNA-Binding Proteins, Dexamethasone, GATA3 Transcription Factor, Gene Expression Regulation, Glucocorticoids, Granulocyte-Macrophage Colony-Stimulating Factor, Hela Cells, Histone Deacetylases, Humans, Immunoprecipitation, Inflammation, Interleukin-13, Interleukin-5, Jurkat Cells, Models, Genetic, Plasmids, Polymerase Chain Reaction, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, RNA, Receptors, Glucocorticoid, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Trans-Activators, Transcription Factor AP-1, Transcription, Genetic, Transfection
J. Biol. Chem.
Date: Jun. 17, 2005
PubMed ID: 15826950
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