Ultradian Cortisol Pulsatility Encodes a Distinct, Biologically Important Signal
Ultradian Cortisol Pulsatility Encodes a Distinct, Biologically Important Signal
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DOI：
10.1371/journal.pone.0015766
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发表时间：
2011-01-18
期刊：
影响因子：
3.7
通讯作者：
Ray, David W.
中科院分区：
文献类型：
--
作者：
McMaster, Andrew;Jangani, Maryam;Ray, David W.
背景：皮质醇在超昼夜脉冲中释放。由此产生的波动的皮质醇浓度的生物相关性尚未explored.Objective：测定ultradian皮质醇pulsatility.Design的生物后果：一种新的流动通过细胞培养系统开发提供ultradian脉冲或连续的皮质醇细胞。皮质醇动力学对细胞增殖和存活以及对基因表达的影响被确定。此外，对糖皮质激素受体（GR）的表达水平和磷酸化，作为一个潜在的调解人的影响，measured.Results：脉动皮质醇引起细胞存活率显着降低相比，连续暴露相同的累积剂量，由于增加细胞凋亡。通过微阵列对转录组反应的综合分析，鉴定了对脉动与连续糖皮质激素递送具有差异反应的基因。用qRT-PCR证实了这些结果。在这些差异调节的靶基因中富集了几个转录因子结合位点，包括CCAAT-置换蛋白（CDP）。CDP调节的报告基因（MMTV-LUC），如预测的那样，也差异调节脉动相比，连续皮质醇输送。重要的是，皮质醇传递动力学对GR表达或激活（GR磷酸化Ser（211））没有影响。结论：皮质醇振荡对靶细胞基因表达和表型产生重要影响。这不是由于累积皮质醇暴露的差异，或表达，或GR的激活。这表明一种新的手段来调节GR功能。
Context: Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.Objective: Determination of the biological consequences of ultradian cortisol pulsatility.Design: A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.Results: Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)).Conclusions: Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function.