p65-activated histone acetyltransferase activity is repressed by glucocorticoids: mifepristone fails to recruit HDAC2 to the p65-HAT complex.
Glucocorticoids acting through their specific receptor can either enhance or repress gene transcription. Dexamethasone represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor expression through a combination of direct inhibition of p65-associated histone acetyltransferase (HAT) activity and by recruiting histone deacetylase 2 (HDAC2) to the p65-HAT complex. Here we show that mifepristone, a glucocorticoid receptor partial agonist, has no ability to induce gene expression but represses interleukin-1beta-stimulated histone acetylation and granulocyte-macrophage colony-stimulating factor release by 50% maximally. Mifepristone was able to inhibit p65-associated HAT activity to the same extent as dexamethasone but failed to inhibit the natural promoter to an equal extent due to an inability to recruit HDAC2 to the p65-associated HAT complex. These data suggest that the maximal repressive actions of glucocorticoids require recruitment of HDAC2 to a p65-HAT complex. These data also suggest that pharmacological manipulation 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 and Lung Institute, Dovehouse St., London SW3 6LY, United Kingdom.
Jazrawi
E
E
Cosio
B
B
Barnes
P J
PJ
Adcock
I M
IM
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051548:Histone Acetyltransferases; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy; D007375:Interleukin-1 / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002843:Chromatin; D005938:Glucocorticoids; D006657:Histones; D006727:Hormone Antagonists; D007375:Interleukin-1; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D051996:Transcription Factor RelA; D015735:Mifepristone; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D008239:Lysine