Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression.
Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression.
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组蛋白脱乙酰基酶2介导的糖皮质激素受体的脱乙酰基化可以抑制NF-kappab。
DOI：
10.1084/jem.20050466
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发表时间：
2006-01-23
影响因子：
15.3
通讯作者：
Adcock, Ian M
中科院分区：
文献类型：
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作者：
Ito, Kazuhiro;Yamamura, Satoshi;Essilfie-Quaye, Sarah;Cosio, Borja;Ito, Misako;Barnes, Peter J;Adcock, Ian M
糖皮质激素是治疗慢性炎症性疾病最有效的抗炎药物，尽管一些疾病，如慢性阻塞性肺疾病（COPD），对糖皮质激素相对不敏感。然而，这种糖皮质激素不敏感的分子机制仍不确定。我们发现，由组蛋白去乙酰化酶（HDAC） 2受损引起的糖皮质激素受体（GR）去乙酰化缺陷导致糖皮质激素对核因子(NF)-κ b介导的基因表达不敏感。通过RNA干扰特异性敲低HDAC2导致对地塞米松抑制白细胞介素1β诱导的粒细胞/巨噬细胞集落刺激因子产生的敏感性降低。HDAC2缺失不减少GR核易位、GR与DNA上的糖皮质激素反应元件（GRE）结合、GR诱导的DNA或基因诱导，但抑制GR与NF-κB的关联。配体结合后GR发生乙酰化，hdac2介导的GR去乙酰化使GR与NF-κB复合物结合。K494和K495的定点突变降低了GR乙酰化，抑制NF-κ b依赖性基因表达的能力对组蛋白去乙酰化酶抑制不敏感。总之，我们发现在COPD患者糖皮质激素不敏感的肺泡巨噬细胞中过表达HDAC2能够恢复糖皮质激素敏感性。因此，HDAC2的减少在抑制NF-κ b介导的而非gre介导的基因表达的糖皮质激素不敏感中起关键作用。
Glucocorticoids are the most effective antiinflammatory agents for the treatment of chronic inflammatory diseases even though some diseases, such as chronic obstructive pulmonary disease (COPD), are relatively glucocorticoid insensitive. However, the molecular mechanism of this glucocorticoid insensitivity remains uncertain. We show that a defect of glucocorticoid receptor (GR) deacetylation caused by impaired histone deacetylase (HDAC) 2 induces glucocorticoid insensitivity toward nuclear factor (NF)-κB–mediated gene expression. Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1β–induced granulocyte/macrophage colony-stimulating factor production. Loss of HDAC2 did not reduce GR nuclear translocation, GR binding to glucocorticoid response element (GRE) on DNA, or GR-induced DNA or gene induction but inhibited the association between GR and NF-κB. GR becomes acetylated after ligand binding, and HDAC2-mediated GR deacetylation enables GR binding to the NF-κB complex. Site-directed mutagenesis of K494 and K495 reduced GR acetylation, and the ability to repress NF-κB–dependent gene expression becomes insensitive to histone deacetylase inhibition. In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity. Thus, reduction of HDAC2 plays a critical role in glucocorticoid insensitivity in repressing NF-κB–mediated, but not GRE-mediated, gene expression.