Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signalling and involves histone deacetylase recruitment

TY - JOUR

T1 - Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signalling and involves histone deacetylase recruitment

AU - Jee, Young-Koo

AU - Gilmour, Jane

AU - Kelly, Audrey

AU - Bowen, Holly

AU - Richards, David

AU - Soh, Cecilia

AU - Smith, Philip

AU - Hawrylowicz, Catherine

AU - Cousins, David

AU - Lee, Tak

AU - Lavender, Paul

PY - 2005/6/17

Y1 - 2005/6/17

N2 - 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.

AB - 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.

KW - Binding Sites

KW - CD4-Positive T-Lymphocytes

KW - Cell Differentiation

KW - Cell Nucleus

KW - Cytokines

KW - DNA

KW - DNA, Complementary

KW - DNA-Binding Proteins

KW - Dexamethasone

KW - GATA3 Transcription Factor

KW - Gene Expression Regulation

KW - Glucocorticoids

KW - Granulocyte-Macrophage Colony-Stimulating Factor

KW - HeLa Cells

KW - Histone Deacetylases

KW - Humans

KW - Immunoprecipitation

KW - Inflammation

KW - Interleukin-13

KW - Interleukin-5

KW - Jurkat Cells

KW - Models, Genetic

KW - Plasmids

KW - Polymerase Chain Reaction

KW - Promoter Regions, Genetic

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - RNA

KW - Receptors, Glucocorticoid

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Signal Transduction

KW - Trans-Activators

KW - Transcription Factor AP-1

KW - Transcription, Genetic

KW - Transfection

U2 - 10.1074/jbc.M503659200

DO - 10.1074/jbc.M503659200

M3 - Article

C2 - 15826950

SN - 1083-351X

VL - 280

SP - 23243

EP - 23250

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 24

ER -