Sonneveld Edwin, Jonas Arjen, Meijer Onno C, Brouwer Abraham, van der Burg Bart
BioDetection Systems B.V., Amsterdam, the Netherlands.
Toxicol Sci. 2007 Oct;99(2):455-69. doi: 10.1093/toxsci/kfm176. Epub 2007 Aug 9.
The aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) are ligand-activated transcription factors and members of the basic helix-loop-helix Period-aryl hydrocarbon nuclear translocator-single minded and nuclear hormone receptor superfamilies, respectively. Besides their individual role as activators of specific gene transcription, also interplay between both transcription factors can be an important mechanism of regulation. In this study, we report that GR can strongly activate AhR-mediated transcription and consequent gene expression in rat H4IIe cells. Reporter gene assays showed an enhanced effect of dexamethasone on the dioxin response mediated by GR in rat H4IIe cells and mouse Hepa 1c1c7 cells, but not in human HepG2 cells and human T47D cells. These deviations between the rodent and human cell lines were confirmed by CYP1A1 enzyme activities. In addition, quantitative reverse transcription-PCR showed enhanced GR-mediated effects of dexamethasone on endogenous 2,3,7,8-tetrachlorodibenzo-[p]-dioxin target genes as well in rat H4IIe cells, but not in human HepG2 and human T47D cells. Surprisingly, AhR itself was upregulated by combined dioxin/glucocorticoid exposure in rat H4IIe cells but not in the human cells which could be explained by the presence of two putative glucocorticoid response elements in the rat AhR promoter, but not in the human AhR promoter. This GR-mediated expression of dioxin target genes through upregulation of the AhR in rat but not in human cells opens the possibility that dioxin responses in rodent-based models for toxicity differ from humans and provides new insight into the interactions of stress-related pathways, biological effects of dioxin-like compounds and may possibly have implications for risk assessment.
芳烃受体（AhR）和糖皮质激素受体（GR）是配体激活的转录因子，分别属于碱性螺旋-环-螺旋周期-芳烃核转运体-单 minded 和核激素受体超家族。除了它们作为特定基因转录激活剂的个体作用外，两种转录因子之间的相互作用也可能是一种重要的调节机制。在本研究中，我们报告 GR 可以强烈激活大鼠 H4IIe 细胞中 AhR 介导的转录及随后的基因表达。报告基因检测显示，地塞米松对大鼠 H4IIe 细胞和小鼠 Hepa 1c1c7 细胞中 GR 介导的二噁英反应有增强作用，但在人 HepG2 细胞和人 T47D 细胞中则没有。CYP1A1 酶活性证实了啮齿动物和人类细胞系之间的这些差异。此外，定量逆转录 PCR 显示，地塞米松对大鼠 H4IIe 细胞中内源性 2,3,7,8-四氯二苯并-p-二噁英靶基因的 GR 介导作用增强，但在人 HepG2 和人 T47D 细胞中则没有。令人惊讶的是，在大鼠 H4IIe 细胞中，二噁英/糖皮质激素联合暴露可上调 AhR 本身，但在人细胞中则不然，这可以通过大鼠 AhR 启动子中存在两个假定的糖皮质激素反应元件来解释，而人 AhR 启动子中则没有。GR 通过上调大鼠而非人细胞中的 AhR 介导二噁英靶基因的表达，这表明基于啮齿动物的毒性模型中的二噁英反应可能与人类不同，并为应激相关途径的相互作用、二噁英类化合物的生物学效应提供了新的见解，可能对风险评估也有影响。
