The aryl hydrocarbon receptor (AhR) is an environmental sensor and ligand-activated transcription factor that is critically involved in the regulation of inflammatory responses and the induction of tolerance by modulating immune cells. As dendritic cells (DCs) express high AhR levels, they are efficient to induce immunomodulatory effects after being exposed to AhR-activating compounds derived from the environment or diet. To gain new insights into the molecular targets following AhR-activation in human monocyte-derived (mo)DCs, we investigated whether the natural AhR ligand quercetin or the synthetic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) modulates the function of human moDCs regarding their capability to prime naïve T cells or to migrate. As only quercetin, but not TCDD, impaired T cell activation and migration of LPS-matured DCs (LPS-DCs), we analyzed the mode of action of quercetin on moDCs in more detail. Here, we found a specific down-regulation of the immunomodulatory molecule CD83 through the direct binding of the activated AhR to the CD83 promoter. Furthermore, treatment of LPS-DCs with quercetin resulted in a reduced production of the pro-inflammatory cytokine IL-12p70 and in an increased expression of the immunoregulatory molecules disabled adaptor protein (Dab) 2, immunoglobulin-like transcript (ILT)-3, ILT4, ILT5 as well as ectonucleotidases CD39 and CD73, thereby inducing a tolerogenic phenotype in quercetin-treated maturing DCs. Overall, these data demonstrate that quercetin represents a potent immunomodulatory agent to alter human DC phenotype and function, shifting the immune balance from inflammation to resolution.

中文翻译：

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槲皮素在成熟的人类树突细胞中诱导免疫调节表型。

芳烃受体 (AhR) 是一种环境传感器和配体激活的转录因子，通过调节免疫细胞参与炎症反应的调节和耐受性的诱导。由于树突细胞 (DC) 表达高水平的 AhR，因此在暴露于来自环境或饮食的 AhR 激活化合物后，它们可有效诱导免疫调节作用。为了对人类单核细胞衍生 (mo) DC 中 AhR 激活后的分子靶标有新的了解，我们研究了天然 AhR 配体槲皮素还是合成配体 2,3,7,8-四氯二苯并对二恶英 (TCDD)调节人类 moDC 的功能，使其能够启动幼稚 T 细胞或迁移。仅作为槲皮素，而不是 TCDD，LPS 成熟 DC (LPS-DC) 的 T 细胞活化和迁移受损，我们更详细地分析了槲皮素对 moDC 的作用模式。在这里，我们发现通过激活的 AhR 与 CD83 启动子的直接结合，免疫调节分子 CD83 的特异性下调。此外，用槲皮素处理 LPS-DC 导致促炎细胞因子 IL-12p70 的产生减少，并导致免疫调节分子禁用衔接蛋白 (Dab) 2、免疫球蛋白样转录物 (ILT)-3 的表达增加， ILT4、ILT5 以及外核苷酸酶 CD39 和 CD73，从而在槲皮素处理的成熟 DC 中诱导致耐受表型。总的来说，这些数据表明槲皮素是一种有效的免疫调节剂，可以改变人类 DC 表型和功能，