Jin Hong Lan, Choi Yujin, Jeong Kwang Won
Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Republic of Korea.
Int J Endocrinol. 2017;2017:5679517. doi: 10.1155/2017/5679517. Epub 2017 Mar 22.
The aryl hydrocarbon receptor (AHR) is known to mediate the cellular reaction involved in processing environmental contaminants and, ultimately, preventing accumulation of unfavorable extra lipids and proteins. Glucocorticoid receptor (GR) mediates the expression of genes associated with anti-inflammatory properties. Because AHR and GR are closely related in lipid metabolic dysregulation and inflammation, we speculate that AHR and GR may play a crucial role in AMD pathogenesis and focus on their crosstalk in human retinal pigment epithelial cells (ARPE-19). However, how AHR and GR regulate each other's signaling pathways is still poorly understood. In this research, we demonstrate that GR attenuates AHR-mediated gene expression by inhibition of nuclear translocation of AHR mediated by TCDD. Chromatin immunoprecipitation analysis demonstrated that GR repress AHR recruitment and chromatin accessibility response to TCDD + Dex treatment leading to repression of AHR target genes. In contrast, AHR facilitates GR-mediated expression in ARPE-19. AHR increases GR recruitment on GRE of GR target genes. Coimmunoprecipitation assay revealed that AHR is associated with GR in ARPE-19 cells and the interaction is enhanced by the addition of TCDD and Dex. Taken together, these studies provide a molecular mechanism of crosstalk between AHR and GR in target gene expression in ARPE-19 cells.
已知芳烃受体（AHR）介导参与处理环境污染物的细胞反应，并最终防止不利的额外脂质和蛋白质积累。糖皮质激素受体（GR）介导与抗炎特性相关的基因表达。由于AHR和GR在脂质代谢失调和炎症方面密切相关，我们推测AHR和GR可能在年龄相关性黄斑变性（AMD）发病机制中起关键作用，并着重研究它们在人视网膜色素上皮细胞（ARPE - 19）中的相互作用。然而，AHR和GR如何相互调节彼此的信号通路仍知之甚少。在本研究中，我们证明GR通过抑制由2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）介导的AHR核转位来减弱AHR介导的基因表达。染色质免疫沉淀分析表明，GR抑制AHR募集以及对TCDD + 地塞米松（Dex）处理的染色质可及性反应，从而导致AHR靶基因的抑制。相反，AHR促进ARPE - 19中GR介导的表达。AHR增加GR在GR靶基因糖皮质激素反应元件（GRE）上的募集。免疫共沉淀试验表明，AHR在ARPE - 19细胞中与GR相关，并且添加TCDD和Dex可增强这种相互作用。综上所述，这些研究提供了ARPE - 19细胞中AHR和GR在靶基因表达中相互作用的分子机制。
