The aryl hydrocarbon receptor (AhR) is a ligand-binding protein that responds to environmental aromatic hydrocarbons and stimulates the transcription of downstream phase I enzyme–related genes by binding the cis element of dioxin-responsive elements (DREs)/xenobiotic-responsive elements. Dimethyl sulfoxide (DMSO) is a well-known organic solvent that is often used to dissolve phase I reagents in toxicology and oxidative stress research experiments. In the current study, we discovered that 0.1% DMSO significantly induced the activation of the AhR promoter via DREs and produced reactive oxygen species, which induced apoptosis in mouse embryonic fibroblasts (MEFs). Moreover, Jun dimerization protein 2 (Jdp2) was found to be required for activation of the AhR promoter in response to DMSO. Coimmunoprecipitation and chromatin immunoprecipitation studies demonstrated that the phase I–dependent transcription factors, AhR and the AhR nuclear translocator, and phase II–dependent transcription factors such as nuclear factor (erythroid-derived 2)–like 2 (Nrf2) integrated into DRE sites together with Jdp2 to form an activation complex to increase AhR promoter activity in response to DMSO in MEFs. Our findings provide evidence for the functional role of Jdp2 in controlling the AhR gene via Nrf2 and provide insights into how Jdp2 contributes to the regulation of ROS production and the cell spreading and apoptosis produced by the ligand DMSO in MEFs.

Graphical abstract

中文翻译：

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二甲基亚砜刺激 AhR-Jdp2 轴以控制小鼠胚胎成纤维细胞中 ROS 的积累

芳烃受体 (AhR) 是一种配体结合蛋白，可对环境芳香烃作出反应，并通过与顺式结合来刺激下游 I 期酶相关基因的转录。二恶英反应元素（DREs）/外源性反应元素的元素。二甲基亚砜 (DMSO) 是一种众所周知的有机溶剂，常用于溶解毒理学和氧化应激研究实验中的 I 相试剂。在目前的研究中，我们发现 0.1% DMSO 通过 DRE 显着诱导 AhR 启动子的激活并产生活性氧，从而诱导小鼠胚胎成纤维细胞 (MEF) 凋亡。此外，发现 Jun 二聚化蛋白 2 (Jdp2) 是响应 DMSO 激活 AhR 启动子所必需的。免疫共沉淀和染色质免疫沉淀研究表明，I 期依赖性转录因子 AhR 和 AhR 核转运蛋白，和 II 期依赖性转录因子，例如核因子（红细胞衍生 2）样 2（Nrf2）与 Jdp2 一起整合到 DRE 位点，形成激活复合物，以增加 AhR 启动子对 MEF 中 DMSO 的反应活性。我们的研究结果为 Jdp2 在通过 Nrf2 控制 AhR 基因中的功能作用提供了证据，并提供了对 Jdp2 如何促进 MEF 中配体 DMSO 产生的 ROS 产生和细胞扩散和细胞凋亡的调节的见解。

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