Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Cell Death Dis. 2018 Aug 30;9(9):890. doi: 10.1038/s41419-018-0814-4.
Alpinetin, a flavonoid compound extracted from the seeds of Alpinia katsumadai Hayata, has been demonstrated to exert massive biological properties. This study aimed to evaluate the effect of alpinetin on dextran sulfate sodium (DSS)-induced colitis, and elucidate the potential mechanisms. Alpinetin significantly alleviated colitis in mice, accompanied with restored Th17/Treg balance in colons. In vitro, alpinetin directly promoted Treg differentiation but exerted little effect on Th17 differentiation, and the action was in an aryl hydrocarbon receptor (AhR)-dependent manner. It acted as a potential AhR activator, evidenced by increased expression of CYP1A1, dissociation of AhR/HSP90 complexes, AhR nuclear translocation, XRE-driven luciferase reporter gene and DNA-binding activity of AhR/ARNT/XRE in T cells. Furthermore, alpinetin significantly promoted expression of miR-302 but not others, and restrained expression of DNMT-1 and methylation level of Foxp3 promoter region in CD4 T cells and colons of colitis mice. However, the association of CREB and Foxp3 promoter region but not expression, nuclear translocation and DNA-binding activity of CREB was up-regulated by alpinetin in CD4 T cells. The relationship of alpinetin-adjusted AhR activation, expressions of miR-302 and DNMT-1, association of CREB and Foxp3 promoter region, and Treg differentiation was confirmed by using CH223191, siAhR, miR-302 inhibitor and pcDNA3.1(+)-mDNMT-1. Finally, CH223191 abolished the amelioration of alpinetin on colitis, induction of Treg cells and regulation of miR-302/DNMT-1/CREB signals in colons of colitis mice. In conclusion, alpinetin ameliorated colitis in mice via activating AhR, regulating miR-302/DNMT-1/CREB signals, therefore promoting Treg differentiation.
山姜素是从益智种子中提取的一种黄酮类化合物，已被证明具有广泛的生物学特性。本研究旨在评估山姜素对葡聚糖硫酸钠（DSS）诱导的结肠炎的影响，并阐明其潜在机制。山姜素显著缓解了小鼠的结肠炎，伴随着结肠中 Th17/Treg 平衡的恢复。在体外，山姜素直接促进 Treg 分化，但对 Th17 分化影响不大，作用方式依赖于芳香烃受体（AhR）。它作为一种潜在的 AhR 激活剂，表现在 CYP1A1 的表达增加，AhR/HSP90 复合物的解离，AhR 核易位，XRE 驱动的荧光素酶报告基因和 AhR/ARNT/XRE 在 T 细胞中的 DNA 结合活性。此外，山姜素显著促进了 miR-302 的表达，但不促进其他 miR 的表达，抑制了 CD4 T 细胞和结肠炎小鼠结肠中 DNMT-1 的表达和 Foxp3 启动子区域的甲基化水平。然而，山姜素在 CD4 T 细胞中上调了 CREB 与 Foxp3 启动子区域的结合，但不影响 CREB 的表达、核易位和 DNA 结合活性。通过使用 CH223191、siAhR、miR-302 抑制剂和 pcDNA3.1(+)-mDNMT-1，证实了山姜素调节的 AhR 激活、miR-302 和 DNMT-1 的表达、CREB 与 Foxp3 启动子区域的结合以及 Treg 分化之间的关系。最后，CH223191 消除了山姜素对结肠炎的改善作用，诱导 Treg 细胞，并调节结肠炎小鼠结肠中 miR-302/DNMT-1/CREB 信号。总之，山姜素通过激活 AhR、调节 miR-302/DNMT-1/CREB 信号，从而促进 Treg 分化，改善了小鼠的结肠炎。
