Differential effects of antidepressants on glucocorticoid receptors in human primary blood cells and human monocytic U-937 cells
Differential effects of antidepressants on glucocorticoid receptors in human primary blood cells and human monocytic U-937 cells
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DOI：
10.1038/sj.npp.1300056
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发表时间：
2003-04-01
影响因子：
7.6
通讯作者：
Vedder, H
中科院分区：
文献类型：
--
作者：
Heiske, A;Jesberg, J;Vedder, H
许多数据支持这样的假设，即抗抑郁药（AD）通过直接作用于糖皮质激素受体（GR），使参与抑郁症病理生理学的下丘脑-垂体-肾上腺皮质（HPA）系统的改变功能正常化。在本研究中，我们研究了三环类AD地昔帕明（DESI）和丙咪嗪（IMI），去甲肾上腺素再摄取抑制剂马普替林（MAPRO），和去甲肾上腺素能和特异性肾上腺素能AD（NaSSA）米氮平（MIR）对原代人白细胞和单核细胞U-937细胞GR表达的影响。半定量RT-PCR结果表明，ADs对原代人白细胞和U-937细胞中GR-mRNA水平的影响不同：MAPRO和IMI未引起GR-mRNA水平的明显变化，DESI和MIR显著降低了两种细胞系统中GR-mRNA的含量。MIR作用的进一步表征揭示了调节的时间依赖性，在处理2，5 h后GR-mRNA水平初始增加至高于对照水平，在孵育4、24和48 h后降低。剂量反应分析表明，浓度为10（-7）M时MIR的最大效应。免疫组织化学研究表明，MIR增加GR蛋白水平的时间依赖性的方式，这种上调出现更早的额外治疗与地塞米松（DEX）。分别在用MIR和MIR/DEX处理的24和48小时之间诱导GR蛋白从细胞质易位到细胞核。综上所述，我们的数据进一步支持了这样的假设，即AD通过影响细胞GR来影响神经内分泌和免疫系统。
A number of data support the assumption that antidepressants (ADs) normalize the altered function of the hypothalamic-pituitary-adrenocortical (HPA) system involved in the pathophysiology of depressive disorder via direct effects on glucocorticoid receptors (GRs). In the present study, we examined the tricyclic ADs desipramine (DESI) and imipramine (IMI), the noradrenaline reuptake inhibitor maprotiline (MAPRO), and the noradrenergic and specific serotonergic AD (NaSSA) mirtazapine (MIR) for their effects on GR expression in primary human leukocytes and in monocytic U-937 cells. Semiquantitative RT-PCR indicated that the ADs exert differential effects on GR-mRNA levels in both primary human leukocytes and U-937 cells: whereas MAPRO and IMI did not induce pronounced changes in GR-mRNA levels, DESI and MIR significantly decreased the amounts of GR-mRNA in both cell systems. Further characterization of the effects of MIR revealed a time dependency of the regulation with an initial increase of GR-mRNA levels above control levels after 2,5 h of treatment and a decrease after 4, 24, and 48 h of incubation. A dose-response analysis demonstrated maximal effects of MIR at a concentration of 10(-7) M. Immunohistochemical studies showed that MIR increased the GR protein levels in a time-dependent manner and that this upregulation appeared earlier by additional treatment with dexamethasone (DEX). A translocation of the GR protein from the cytoplasm to the nucleus was induced between 24 and 48 h of treatment with MIR and MIR/DEX, respectively. Taken together, our data further support the assumption that ADs influence the neuroendocrine and immune system via effects on cellular GRs.