Mechanisms of tissue factor induction by the uremic toxin indole-3 acetic acid through aryl hydrocarbon receptor/nuclear factor-kappa B signaling pathway in human endothelial cells
Mechanisms of tissue factor induction by the uremic toxin indole-3 acetic acid through aryl hydrocarbon receptor/nuclear factor-kappa B signaling pathway in human endothelial cells
复制标题
尿毒症毒素吲哚-3-乙酸通过芳烃受体/核因子-kappaB信号通路诱导内皮细胞产生组织因子的机制
DOI：
10.1007/s00204-018-2328-3
复制
发表时间：
2019-01-01
影响因子：
6.1
通讯作者：
Dou, Laetitia
中科院分区：
文献类型：
--
作者：
Addi, Tawfik;Poitevin, Stephane;Dou, Laetitia
慢性肾脏病（CKD）与血栓形成的高风险相关。吲哚乙酸（Indole-3 Acetic Acid，IAA）是一种吲哚类尿毒症毒素，可通过转录因子芳烃受体（Arylhydrocarbon receptor，AhR）诱导人脐静脉内皮细胞（human umbilical vein endothelial cells，HUVEC）表达组织因子（tissue factor，TF）。本研究旨在了解IAA诱导AhR介导TF的信号通路。我们将人内皮细胞与50 μ M的IAA孵育，这是CKD患者中发现的最大浓度。IAA诱导TF在不同类型的人内皮细胞中表达：脐静脉（HUVEC）、主动脉（HAoEC）和心脏衍生的微血管（HMVEC-C）。使用AhR抑制和染色质免疫沉淀实验，我们表明，TF诱导IAA在HUVEC中是由AhR控制，AhR不结合TF启动子。利用荧光素酶报告质粒对TF启动子活性的分析表明，NF-B位点在IAA诱导TF中是必不可少的。此外，转录因子诱导的IAA显着降低了抑制剂的NF-B途径。IAA诱导NF-B p50亚基核转位，AhR和p38 MAPK抑制可降低NF-B p50亚基核转位。最后，在92例接受血液透析的CKD患者队列中，多变量分析显示循环TF与血清IAA独立相关。总之，TF上调IAA在人内皮细胞中涉及非基因组AhR/p38 MAPK/NF-B途径。了解与AhR血栓/炎症通路相关的信号转导通路对于寻找降低CKD患者TF表达和血栓形成风险的治疗靶点具有重要意义。
Chronic kidney disease (CKD) is associated with high risk of thrombosis. Indole-3 acetic acid (IAA), an indolic uremic toxin, induces the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVEC) via the transcription factor aryl hydrocarbon receptor (AhR). This study aimed to understand the signaling pathways involved in AhR-mediated TF induction by IAA. We incubated human endothelial cells with IAA at 50 mu M, the maximal concentration found in patients with CKD. IAA induced TF expression in different types of human endothelial cells: umbilical vein (HUVEC), aortic (HAoEC), and cardiac-derived microvascular (HMVEC-C). Using AhR inhibition and chromatin immunoprecipitation experiments, we showed that TF induction by IAA in HUVEC was controlled by AhR and that AhR did not bind to the TF promoter. The analysis of TF promoter activity using luciferase reporter plasmids showed that the NF-B site was essential in TF induction by IAA. In addition, TF induction by IAA was drastically decreased by an inhibitor of the NF-B pathway. IAA induced the nuclear translocation of NF-B p50 subunit, which was decreased by AhR and p38MAPK inhibition. Finally, in a cohort of 92 CKD patients on hemodialysis, circulating TF was independently related to serum IAA in multivariate analysis. In conclusion, TF up-regulation by IAA in human endothelial cells involves a non-genomic AhR/p38 MAPK/NF-B pathway. The understanding of signal transduction pathways related to AhR thrombotic/inflammatory pathway is of interest to find therapeutic targets to reduce TF expression and thrombotic risk in patients with CKD.