Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand that Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling
Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand that Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling
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DOI：
10.1093/toxsci/kfq024
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发表时间：
2010-05-01
影响因子：
3.8
通讯作者：
Perdew, Gary H.
中科院分区：
文献类型：
--
作者：
DiNatale, Brett C.;Murray, Iain A.;Perdew, Gary H.
炎症信号在肿瘤进展中起关键作用，多效细胞因子白介素-6 （IL-6）是致瘤特性的重要介质。外源性配体结合炎症信号激活芳烃受体（AHR）可协同诱导肿瘤细胞中IL6的表达。是否存在内源性AHR配体介导IL6的产生还有待进一步研究。吲哚胺-2,3-双加氧酶途径是一种色氨酸氧化途径，参与控制免疫耐受，也有助于肿瘤逃逸。我们筛选了该途径的代谢物，以了解它们激活AHR的能力；结果表明，犬尿酸（KA）是一种有效的人AHR激动剂。结构活性研究进一步表明，羧酸基团是显著的激动剂活性所必需的。KA能够在HepG2细胞中诱导CYP1A1信使RNA水平，并在人原代肝细胞中诱导CYP1A1介导的代谢。在人类二恶英反应元件驱动的稳定报告细胞系中，观察到EC25为104nM，而在小鼠稳定报告细胞系中，EC25为10 μ m。用白细胞介素-1 β和生理相关浓度的KA（例如，100nM）处理MCF-7细胞可诱导IL6表达，这在很大程度上依赖于AHR的表达。我们的研究结果表明，KA是一种有效的AHR内源性配体，可以在生理相关浓度下诱导细胞中IL6的产生和异种代谢。
Inflammatory signaling plays a key role in tumor progression, and the pleiotropic cytokine interleukin-6 (IL-6) is an important mediator of protumorigenic properties. Activation of the aryl hydrocarbon receptor (AHR) with exogenous ligands coupled with inflammatory signals can lead to synergistic induction of IL6 expression in tumor cells. Whether there are endogenous AHR ligands that can mediate IL6 production remains to be established. The indoleamine-2,3-dioxygenase pathway is a tryptophan oxidation pathway that is involved in controlling immune tolerance, which also aids in tumor escape. We screened the metabolites of this pathway for their ability to activate the AHR; results revealed that kynurenic acid (KA) is an efficient agonist for the human AHR. Structure-activity studies further indicate that the carboxylic acid group is required for significant agonist activity. KA is capable of inducing CYP1A1 messenger RNA levels in HepG2 cells and inducing CYP1A-mediated metabolism in primary human hepatocytes. In a human dioxin response element-driven stable reporter cell line, the EC25 was observed to be 104nM, while in a mouse stable reporter cell line, the EC25 was 10 mu M. AHR ligand competition binding assays revealed that KA is a ligand for the AHR. Treatment of MCF-7 cells with interleukin-1 beta and a physiologically relevant concentration of KA (e.g., 100nM) leads to induction of IL6 expression that is largely dependent on AHR expression. Our findings have established that KA is a potent AHR endogenous ligand that can induce IL6 production and xenobiotic metabolism in cells at physiologically relevant concentrations.