title: Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signaling and involves histone deacetylase recruitment.
abstract: 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.
authors.affiliation: Department of Asthma, Allergy, and Respiratory Science, King's College London, 5th Floor, Thomas Guy House, Guy's Hospital, UK.
authors.forename: Young-Koo
authors.initials: YK
authors.lastname: Jee
authors.forename: Jane
authors.initials: J
authors.lastname: Gilmour
authors.forename: Audrey
authors.initials: A
authors.lastname: Kelly
authors.forename: Holly
authors.initials: H
authors.lastname: Bowen
authors.forename: David
authors.initials: D
authors.lastname: Richards
authors.forename: Cecilia
authors.initials: C
authors.lastname: Soh
authors.forename: Philip
authors.initials: P
authors.lastname: Smith
authors.forename: Catherine
authors.initials: C
authors.lastname: Hawrylowicz
authors.forename: David
authors.initials: D
authors.lastname: Cousins
authors.forename: Tak
authors.initials: T
authors.lastname: Lee
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
mesh_terms: D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D005938:Glucocorticoids; D018793:Interleukin-13; D015848:Interleukin-5; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D012313:RNA; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D006655:Histone Deacetylases