Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression.
Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression.
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DOI：
10.1371/journal.pone.0161430
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Uht RM
中科院分区：
文献类型：
--
作者：
Stacey W;Bhave S;Uht RM
雌二醇通过抑制促炎基因的表达来减轻炎症反应。鉴于炎症越来越多地与神经退行性和精神过程有关，我们试图阐明E2下调炎症反应的一个组成部分-环氧合酶-2(COX-2)表达的机制。虽然大脑中的炎症过程通常与小胶质细胞和星形胶质细胞有关，但我们发现COX-2基因(COX-2)在神经元背景下表达，特别是在杏仁细胞系(AR-5)中。鉴于COX-2已被报道存在于大脑中的神经元中，并且杏仁核是参与神经退行性变和神经精神过程的部位，我们研究了E2下调AR-5细胞中COX-2表达的机制。这些细胞表达雌激素受体α(ERα)和β(ERβ)，如图所示COX-2。在核糖核酸水平上，雌激素和ER-β选择性配体二芳基丙腈均能抑制基因表达，而ER-α选择性配体丙基吡唑三醇对基因表达无影响。两种配体均不能增加COX-2启动子上的ERβ。相反，DPN减少了NF-κB p65和组蛋白4(H4)乙酰化的启动子占有率。用非特异性HDAC抑制剂曲古抑素A(TSA)处理可拮抗DPN对COX-2表达的抑制作用。与TSA效应相一致的是，E2和DPN增加了组蛋白脱乙酰酶1(HDAC1)和开关非依赖性3A(Sin3A)启动子的占有率。最后，即使E2增加了CpG甲基化，DPN也没有。综上所述，药理学数据表明，ERβ有助于神经元COX-2的表达。此外，内质网配体导致HDAC1和Sin3A的招募增加，并伴随着P65占有率和Ac-H4水平的降低。然而，没有一个事件与ERβ在启动子上的显著招募有关。因此，ERβ将招募定向到COX-2启动子，但在本身没有被招募的情况下这样做。
E2 attenuates inflammatory responses by suppressing expression of pro-inflammatory genes. Given that inflammation is increasingly being associated with neurodegenerative and psychiatric processes, we sought to elucidate mechanisms by which E2 down-regulates a component of an inflammatory response, cyclooxygenase– 2 (COX-2) expression. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, we found that the COX-2 gene (cox-2) was expressed in a neuronal context, specifically in an amygdalar cell line (AR-5). Given that COX-2 has been reported to be in neurons in the brain, and that the amygdala is a site involved in neurodegenerative and neuropsychiatric processes, we investigated mechanisms by which E2 could down-regulate cox-2 expression in the AR-5 line. These cells express estrogen receptors alpha (ERα) and beta (ERβ), and as shown here cox-2. At the level of RNA, E2 and the ERβ selective ligand diarylpropionitrile (DPN) both attenuated gene expression, whereas the ERα selective ligand propyl pyrazole triol (PPT) had no effect. Neither ligand increased ERβ at the cox-2 promoter. Rather, DPN decreased promoter occupancy of NF-κB p65 and histone 4 (H4) acetylation. Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the TSA effect, E2 and DPN increased histone deacetylase one (HDAC1) and switch-independent 3A (Sin3A) promoter occupancy. Lastly, even though E2 increased CpG methylation, DPN did not. Taken together, the pharmacological data indicate that ERβ contributes to neuronal cox-2 expression, as measured by RNA levels. Furthermore, ER ligands lead to increased recruitment of HDAC1, Sin3A and a concomitant reduction of p65 occupancy and Ac-H4 levels. None of the events, however, are associated with a significant recruitment of ERβ at the promoter. Thus, ERβ directs recruitment to the cox-2 promoter, but does so in the absence of being recruited itself.