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

作     者：Ito, K Barnes, PJ Adcock, IM 

作者机构：Natl Heart & Lung Inst Imperial Coll Sch Med London SW3 6LY England 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：2000年第20卷第18期

页      面：6891-6903页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

主　　题：乙酰化作用 乙酰基转移酶类/遗传学 结合部位 CREB结合蛋白质 细胞周期蛋白质类/遗传学 染色质/代谢 地塞米松/代谢 地塞米松/药理学 基因表达/药物作用 粒细胞巨噬细胞集落刺激因子/遗传学 组蛋白酰基转移酶 组蛋白脱乙酰基酶2 组蛋白脱乙酰基酶类/代谢 组蛋白类/代谢 白细胞介素1/代谢 白细胞介素1/药理学 赖氨酸/代谢 NF-κB/代谢 核蛋白质类/遗传学 磷酰化 启动区 遗传 受体 糖皮质激素/代谢 阻遏蛋白质类 反式激活因子类/遗传学 转录因子RelA 转录因子 转录激活/药物作用 肿瘤细胞 培养的 p300-CBP转录因子 人类 

摘      要：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 dexamethasone (10(-10) M) repress IL-1 beta-stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression and fail to stimulate secretory leukocyte proteinase inhibitor expression. Dexamethasone (10(-7) M) and IL-1 beta (1 ng/ml) both stimulated HAT activity but showed a different pattern of histone H4 acetylation. Dexamethasone targeted lysines K5 and K16, whereas IL-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 acetylation. Using chromatin immunoprecipitation assays, we show that dexamethasone inhibits IL-1 beta-enhanced acetylated K8-associated GM-CSF promoter enrichment in a concentration-dependent manner. Neither IL-1 beta 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.