The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase.
The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase.
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DOI：
10.1016/j.toxlet.2015.10.009
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发表时间：
2016-01-05
影响因子：
3.5
通讯作者：
Bast A
中科院分区：
文献类型：
--
作者：
Randall MJ;Haenen GR;Bouwman FG;van der Vliet A;Bast A
慢性阻塞性肺病（COPD）是全世界与吸烟相关的死亡的主要原因。丙烯醛是香烟烟雾中发现的一种重要的反应性亲电子试剂，它模仿了香烟烟雾暴露在肺部的许多毒性作用。在巨噬细胞中，已知香烟烟雾会阻碍组蛋白脱乙酰酶 (HDAC)，这是一种糖皮质激素调节酶，在糖皮质激素抵抗性炎症（慢性阻塞性肺病的一个常见特征）的发病机制中发挥着重要作用。因此，我们假设丙烯醛在慢性阻塞性肺病相关的糖皮质激素抵抗中发挥作用。为了检查丙烯醛对糖皮质激素抵抗的作用，用丙烯醛处理用PMA分化为巨噬细胞样细胞的U937单核细胞0.5小时，然后用氢化可的松刺激8小时，或同时用LPS和氢化可的松在没有丙烯醛的情况下处理8小时。测量 GSH 和核 HDAC 活性，或通过 qPCR 分析基因表达。氢化可的松不抑制丙烯醛介导的 TNFα 基因表达，而 LPS 诱导的 TNFα 表达则受到抑制。丙烯醛还显着抑制巨噬细胞样细胞中的核 HDAC 活性。重组 HDAC2 与丙烯醛一起孵育导致形成 HDAC2-丙烯醛加合物，经质谱鉴定。因此，这些结果表明丙烯醛诱导的炎症基因表达对内源性糖皮质激素氢化可的松的抑制具有抵抗力。
Chronic obstructive pulmonary disease (COPD) is the leading cause of cigarette smoke-related death worldwide. Acrolein, a crucial reactive electrophile found in cigarette smoke mimics many of the toxic effects of cigarette smoke-exposure in the lung. In macrophages, cigarette smoke is known to hinder histone deacetylases (HDACs), glucocorticoid-regulated enzymes that play an important role in the pathogenesis of glucocorticoid resistant inflammation, a common feature of COPD. Thus, we hypothesize that acrolein plays a role in COPD-associated glucocorticoid resistance. To examine the role of acrolein on glucocorticoid resistance, U937 monocytes, differentiated with PMA to macrophage-like cells were treated with acrolein for 0.5 h followed by stimulation with hydrocortisone for 8 h, or treated simultaneously with LPS and hydrocortisone for 8 h without acrolein. GSH and nuclear HDAC activity were measured, or gene expression was analyzed by qPCR. Acrolein-mediated TNFα gene expression was not suppressed by hydrocortisone whereas LPS-induced TNFα expression was suppressed. Acrolein also significantly inhibited nuclear HDAC activity in macrophage-like cells. Incubation of recombinant HDAC2 with acrolein led to the formation of an HDAC2-acrolein adduct identified by mass spectrometry. Therefore, these results suggest that acrolein-induced inflammatory gene expression is resistant to suppression by the endogenous glucocorticoid, hydrocortisone.