Hypoxia-inducible Factor 1α Induces Corticosteroid-insensitive Inflammation via Reduction of Histone Deacetylase-2 Transcription
Hypoxia-inducible Factor 1α Induces Corticosteroid-insensitive Inflammation via Reduction of Histone Deacetylase-2 Transcription
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DOI：
10.1074/jbc.m109.025387
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Ito, Kazuhiro
中科院分区：
文献类型：
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作者：
Charron, Catherine E.;Chou, Pai-Chien;Ito, Kazuhiro
皮质类固醇是有效的抗炎剂，但皮质类固醇不敏感性是治疗某些慢性炎症性疾病的主要障碍。在这里，我们表明，缺氧诱导皮质类固醇不敏感的炎症通过减少组蛋白去乙酰化酶-2（HDAC 2）在肺上皮细胞和巨噬细胞的转录。缺氧条件下（1%O-2）HDAC 2 mRNA和蛋白表达降低。缺氧可促进A549细胞产生白细胞介素-1 β诱导的白细胞介素-8（CXCL 8），并降低地塞米松抑制CXCL 8产生的能力。缺失或点突变研究显示，转录因子缺氧诱导因子（HIF）1 α与位置-320处的HIF应答元件结合，而不是HIF-1 β或HIF-2 α，导致该位点处聚合酶II结合减少，导致HDAC 2启动子活性降低。我们的研究结果表明，缺氧激活HIF-1 α降低HDAC 2水平，导致炎症和皮质类固醇抵抗放大。
Corticosteroids are potent anti-inflammatory agents, but corticosteroid insensitivity is a major barrier for the treatment of some chronic inflammatory diseases. Here, we show that hypoxia induces corticosteroid-insensitive inflammation via reduced transcription of histone deacetylase-2 (HDAC2) in lung epithelial and macrophage cells. HDAC2 mRNA and protein expression was reduced under hypoxic conditions (1% O-2). Hypoxia enhanced interleukin-1 beta-induced interleukin-8 (CXCL8) production in A549 cells and decreased the ability of dexamethasone to suppress the CXCL8 production. Deletion or point mutation studies revealed that binding of the transcription factor hypoxia-inducible factor (HIF) 1 alpha to a HIF response element at position -320, but not HIF-1 beta or HIF-2 alpha, results in reduced polymerase II binding at the site, leading to reduced promoter activity of HDAC2. Our results suggest that activation of HIF-1 alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance.