Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1 beta-induced histone H4 acetylation on lysines 8 and 12

We have investigated the ability of dexamethasone to regulate interleukin-1 beta (IL-1 beta)-induced gene expression, histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity. Low concentrations of dexamethason e (10(-10) M) repress IL-1 beta-stimulated granulocyte-macrophage colony-st imulating factor (GM-CSF) expression and fail to stimulate secretory leukoc yte proteinase inhibitor expression. Dexamethasone (10(-7) M) and IL-1 beta (1 ng/ml) both stimulated HAT activity but showed a different pattern of h istone H4 acetylation. Dexamethasone targeted lysines K5 and K16, whereas I L-1 beta targeted K8 and K12. Low concentrations of dexamethasone (10(-10) M), which do not transactivate, repressed IL-1 beta-stimulated K8 and K12 a cetylation. Using chromatin immunoprecipitation assays, we show that dexame thasone inhibits IL-1 beta-enhanced acetylated K8-associated GM-CSF promote r enrichment in a concentration-dependent manner. Neither IL-1 beta nor dex amethasone elicited any GM-CSF promoter association at acetylated K5 residu es. Furthermore, we show that GR acts both as a direct inhibitor of CREB bi nding 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. T his mechanism for glucocorticoid repression is novel and establishes that i nhibition of histone acetylation is an additional level of control of infla mmatory gene expression. This further suggests that pharmacological manipul ation of of specific histone acetylation status is a potentially useful app roach for the treatment of inflammatory diseases.