Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells.
Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells.
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DOI：
10.1007/s00204-016-1880-y
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发表时间：
2017-05
影响因子：
6.1
通讯作者：
Vogel CFA
中科院分区：
文献类型：
--
作者：
Kado S;Chang WLW;Chi AN;Wolny M;Shepherd DM;Vogel CFA
目前，还没有很好地理解芳基烃受体（AhR）的配体如何修饰人树突状细胞（DC）中由Toll样受体（TLR）激动剂触发的炎症反应。在这里，我们表明，AhR配体2，3，7，8-四氯二苯并-对-二恶英（TCDD），色氨酸衍生物6-甲酰吲哚并[3，2-B]咔唑（FICZ），犬尿氨酸（kyn），和天然膳食化合物吲哚-3-甲醇（I3 C）差异修饰细胞因子在人单核细胞衍生的DC（MoDC）的表达。结果显示TLR激活的MoDC表达更高水平的AhR，并且对AhR配体的作用更敏感。根据细胞因子的不同，AhR配体的治疗导致TLR触发的反应在MoDC中的协同或拮抗作用。因此，AhR的激活增加了TLR激活的MoDC中白细胞介素（IL）-1β的表达，但降低了IL-12 A的表达。此外，TCDD和FICZ可能对TLR 8激活的MoDC中细胞色素P4501 A1（CYP 1A 1）的表达具有相反的作用，表明特定AhR配体的作用可能取决于特定TLR激动剂的存在。基因沉默表明AhR配体对TLR诱导的IL-1β表达的协同作用需要功能性AhR和NF-κB RelB的表达。另一方面，TCDD和FICZ对IL-12 A的抑制涉及尾型同源框2（CDX 2）转录因子的诱导。此外，DC表面标志物的水平在MoDC中被TCDD、FICZ和I3 C降低，但不被kyn降低。总之，这些数据表明AhR调节TLR诱导的MoDC中细胞因子和DC特异性表面标志物的表达，涉及NFκB RelB和免疫调节因子CDX 2。
Currently, it is not well understood how ligands of the Aryl hydrocarbon Receptor (AhR) modify inflammatory responses triggered by Toll like receptor (TLR) agonists in human dendritic cells (DCs). Here, we show that AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the tryptophan derivatives 6-formylindolo[3,2-b]carbazole (FICZ), Kynurenine (kyn), and the natural dietary compound Indole-3-carbinole (I3C) differentially modify cytokine expression in human monocyte-derived DCs (MoDCs). The results show that TLR-activated MoDCs express higher levels of AhR and are more sensitive towards the effects of AhR ligands. Depending on the cytokine, treatment with AhR ligands led to a synergistic or antagonistic effect of the TLR-triggered response in MoDCs. Thus, activation of AhR increased the expression of Interleukin (IL)-1β, but decreased the expression of IL-12A in TLR-activated MoDCs. Furthermore, TCDD and FICZ may have opposite effects on the expression of cytochrome P4501A1 (CYP1A1) in TLR8-activated MoDCs indicating that the effect of the specific AhR ligand may depend on the presence of the specific TLR agonist. Gene silencing showed that synergistic effects of AhR ligands on TLR-induced expression of IL-1β requires a functional AhR and the expression of NF-κB RelB. On the other hand, repression of IL-12A by TCDD and FICZ involved the induction of the caudal type homeobox 2 (CDX2) transcription factor. Additionally, the levels of DC surface markers were decreased in MoDCs by TCDD, FICZ and I3C, but not by kyn. Overall, these data demonstrate that AhR modulates TLR-induced expression of cytokines and DC-specific surface markers in MoDCs involving NFκB RelB and the immune regulatory factor CDX2.