PDF(Pubmed)
Abstract：
Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects. In this study, we designed, synthesized and evaluated three indole-containing potential AHR ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5 actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish embryos and was therefore considered safe for animal studies. Following oral administration to C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1 cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the small intestine). These findings make AGT-5 a promising candidate for further exploration in the treatment of inflammatory and autoimmune diseases.
摘要：
芳基烃受体（AHR）配体，在绑定时，诱导由AHR编排的不同基因表达谱，导致一系列的促炎或抗炎作用。在这项研究中,我们设计的,合成并评估了三种含吲哚的潜在AHR配体(FluoAHRL:AGT-4、AGT-5和AGT-6)。所有合成的化合物均显示在近红外中发射荧光。他们的AHR激动剂活性首先是使用硅对接研究预测的，然后使用AHR荧光素酶报告细胞系进行确认。使用小鼠腹膜巨噬细胞和T淋巴细胞在体外测试荧光AHRL以评估其免疫调节特性。然后，我们专注于AGT-5，因为它说明了主要的抗炎作用。值得注意的是,AGT-5证明了在体外培养抗炎调节性T细胞(Treg)同时抑制促炎辅助性T细胞(Th)17的能力。AGT-5从初始CD4+细胞主动诱导Treg分化，促进Treg增殖，细胞毒性T淋巴细胞相关抗原4（CTLA-4）的表达和白细胞介素10（IL-10）的产生。IL-10的增加与信号转导和转录激活因子3(STAT3)表达的上调相关。重要的是,在体外人扁桃体细胞中也观察到AGT-5的Treg诱导作用。AGT-5在应用于斑马鱼胚胎时没有毒性，因此被认为对动物研究是安全的。口服给C57BL/6小鼠后，AGT-5显著上调Treg,同时下调肠系膜淋巴结中的促炎Th1细胞。由于其荧光特性,AGT-5可以在体外(在巨噬细胞摄取期间)和离体(在小肠的固有层内)可视化。这些发现使AGT-5成为进一步探索炎症和自身免疫性疾病治疗的有希望的候选者。
