p65-activated histone acetyltransferase activity is repressed by glucocorticoids

Glucocorticoids acting through their specific receptor can either enhance o r repress gene transcription. Dexamethasone represses interleukin-1 beta -s timulated histone acetylation and granulocyte-macrophage colony-stimulating factor expression through a combination of direct inhibition of p65-associ ated histone acetyltransferase CHAT) activity and by recruiting histone dea cetylase 2 (HDAC2) to the p65-HAT complex. Here we show that mifepristone, a glucocorticoid receptor partial agonist, has no ability to induce gene ex pression but represses interleukin-1 beta -stimulated histone acetylation a nd granulocyte-macrophage colony-stimulating factor release by 50% maximall y. Mifepristone was able to inhibit p65-associated HAT activity to the same extent as dexamethasone but failed to inhibit the natural promoter to an e qual extent clue to an inability to recruit HDAC2 to the p65-associated HAT complex. These data suggest that the maximal repressive actions of glucoco rticoids 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 d iseases.