Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12.
We have investigated the ability of dexamethasone to regulate interleukin-1beta (IL-1beta)-induced gene expression, histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity. Low concentrations of dexamethasone (10(-10) M) repress IL-1beta-stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression and fail to stimulate secretory leukocyte proteinase inhibitor expression. Dexamethasone (10(-7) M) and IL-1beta (1 ng/ml) both stimulated HAT activity but showed a different pattern of histone H4 acetylation. Dexamethasone targeted lysines K5 and K16, whereas IL-1beta targeted K8 and K12. Low concentrations of dexamethasone (10(-10) M), which do not transactivate, repressed IL-1beta-stimulated K8 and K12 acetylation. Using chromatin immunoprecipitation assays, we show that dexamethasone inhibits IL-1beta-enhanced acetylated K8-associated GM-CSF promoter enrichment in a concentration-dependent manner. Neither IL-1beta nor dexamethasone elicited any GM-CSF promoter association at acetylated K5 residues. Furthermore, we show that GR acts both as a direct inhibitor of CREB binding protein (CBP)-associated HAT activity and also by recruiting HDAC2 to the p65-CBP HAT complex. This action does not involve de novo synthesis of HDAC protein or altered expression of CBP or p300/CBP-associated factor. This mechanism for glucocorticoid repression is novel and establishes that inhibition of histone acetylation is an additional level of control of inflammatory gene expression. This further suggests that pharmacological manipulation of of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases.
Ito
K
K
Thoracic Medicine, Imperial College School of Medicine at the National Heart & Lung Institute, London, United Kingdom.
Barnes
P J
PJ
Adcock
I M
IM
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics; D001665:Binding Sites; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D051548:Histone Acetyltransferases; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012097:Repressor Proteins; D015534:Trans-Activators / Q000235:genetics; D051996:Transcription Factor RelA; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D002843:Chromatin; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051548:Histone Acetyltransferases; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D006657:Histones; D007375:Interleukin-1; D008239:Lysine; D016328:NF-kappa B; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494363:CREBBP protein, human