Effects of representative glucocorticoids on TNFα- and CD40L-induced NF-κB activation in sensor cells.
Effects of representative glucocorticoids on TNFα- and CD40L-induced NF-κB activation in sensor cells.
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DOI：
10.1016/j.steroids.2014.04.003
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发表时间：
2014-07
期刊：
影响因子：
2.7
通讯作者：
Buchwald P
中科院分区：
文献类型：
--
作者：
Cechin SR;Buchwald P
糖皮质激素是一类重要的抗炎/免疫抑制药物。其抗炎作用的一个关键部分是由于其在与糖皮质激素受体（GR）结合后抑制促炎转录因子如核因子-κB（NF-κB）和激活蛋白-1（AP-1）的能力。因此，传感器细胞量化其对炎症信号诱导的NF-κB活化的作用可以提供关于其效力以及其反式阻遏能力的有用信息。在这里，我们报告了在含有NF-κ B诱导型SEAP构建体的感受器细胞中，它们抑制TNFα和CD 40 L诱导的NF-κB活化的效果。在这些细胞中，我们证实了TNFα和CD 40 L在低纳摩尔浓度（EC 50）下的浓度依赖性NF-κB活化。检测的糖皮质激素包括氢化可的松、泼尼松龙、地塞米松、依碳酸氯替泼诺、曲安奈德、丙酸倍氯米松和丙酸氯倍他索。他们都造成了显着的，但只有部分抑制这些激活的浓度依赖性的方式，可以很好地描述了乙状响应函数。尽管仅部分最大抑制的限制，这种基于细胞的测定可用于定量糖皮质激素对由两种不同细胞因子平行引起的促炎性转录因子表达的抑制能力（反式阻遏效力），其以详细的、完整的剂量-反应形式以及以更简单的单剂量形式。尽管在TNF试验中获得的抑制效力与所有化合物的一致糖皮质激素效力（受体结合亲和力，Kd，RBA，在GR）相关性良好，但非卤代类固醇（氢化可的松，泼尼松龙和氯替泼诺）的效力比该系统中CD 40试验中预期的效力高约一个数量级。
Glucocorticoids are an important class of anti-inflammatory/immunosuppressive drugs. A crucial part of their anti-inflammatory action results from their ability to repress proinflammatory transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) upon binding to the glucocorticoid receptor (GR). Accordingly, sensor cells quantifying their effect on inflammatory signal-induced NF-κB activation can provide useful information regarding their potencies as well as their transrepression abilities. Here, we report results obtained on their effect in suppressing both the TNFα- and the CD40L-induced activation of NF-κB in sensor cells that contain an NF-κB–inducible SEAP construct. In these cells, we confirmed concentration-dependent NF-κB activation for both TNFα and CD40L at low nanomolar concentrations (EC50). Glucocorticoids tested included hydrocortisone, prednisolone, dexamethasone, loteprednol etabonate, triamcinolone acetonide, beclomethasone dipropionate, and clobetasol propionate. They all caused significant, but only partial inhibition of these activations in concentration-dependent manners that could be well described by sigmoid response-functions. Despite the limitations of only partial maximum inhibitions, this cell-based assay could be used to quantitate the suppressing ability of glucocorticoids (transrepression potency) on the expression of proinflammatory transcription factors caused by two different cytokines in parallel both in a detailed, full dose-response format as well as in a simpler single-dose format. Whereas inhibitory potencies obtained in the TNF assay correlated well with consensus glucocorticoid potencies (receptor-binding affinities, Kd, RBA, at the GR) for all compounds, the non-halogenated steroids (hydrocortisone, prednisolone, and loteprednol etabonate) were about an order of magnitude more potent than expected in the CD40 assay in this system.
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