Jacob Aude, Potin Sophie, Chapy Hélène, Crete Dominique, Glacial Fabienne, Ganeshamoorthy Kayathiri, Couraud Pierre-Olivier, Scherrmann Jean-Michel, Declèves Xavier
INSERM, UMR-S 1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France.
INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Paris, France.
Brain Res. 2015 Jul 10;1613:27-36. doi: 10.1016/j.brainres.2015.03.049. Epub 2015 Apr 7.
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor activated by a variety of widespread persistent environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It can transactivate the expression of several target genes. Recently AhR transcripts were detected in isolated human brain microvessels and in the hCMEC/D3 human cerebral microvascular endothelial cell line, an in vitro model of the human cerebral endothelium. To date AhR implication in the co-regulation of ABCB1, ABCG2 and CYP1B1 at human cerebral endothelium has not been addressed. Here we investigated whether AhR could co-regulate ABCB1, ABCG2 and CYP1B1 expressions in the hCMEC/D3 cell line. Exposure to TCDD induced a concentration-dependent increase in CYP1B1 expression. We demonstrated AhR involvement in the TCDD-mediated increase in CYP1B1 expression by using small interfering RNA against AhR. Western blotting analysis also revealed an increase in CYP1B1 protein expression following TCDD exposure in hCMEC/D3. Regarding ABCB1 and ABCG2, exposure to TCDD had no effect on their protein expressions and functional activities. In conclusion our data indicated a differential modulation of CYP1B1 and ABCB1/ABCG2 expressions in hCMEC/D3 cells following TCDD exposure.
芳烃受体（AhR）是一种依赖配体的转录因子，可被多种广泛存在的持久性环境污染物激活，如2,3,7,8-四氯二苯并对二恶英（TCDD）。它可以反式激活多个靶基因的表达。最近，在分离出的人脑微血管以及人脑血管内皮细胞体外模型hCMEC/D3细胞系中检测到了AhR转录本。迄今为止，尚未研究AhR在人脑血管内皮细胞中对ABCB1、ABCG2和CYP1B1的共同调节作用。在此，我们研究了AhR是否能在hCMEC/D3细胞系中共同调节ABCB1、ABCG2和CYP1B1的表达。暴露于TCDD会导致CYP1B1表达呈浓度依赖性增加。我们通过使用针对AhR的小干扰RNA证明了AhR参与了TCDD介导的CYP1B1表达增加。蛋白质印迹分析还显示，hCMEC/D3细胞暴露于TCDD后，CYP1B1蛋白表达增加。关于ABCB1和ABCG2，暴露于TCDD对它们的蛋白表达和功能活性没有影响。总之，我们的数据表明，hCMEC/D3细胞暴露于TCDD后，CYP1B1和ABCB1/ABCG2的表达受到不同调节。
