Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation
Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation
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DOI：
10.1111/all.12162
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发表时间：
2013-07-01
期刊：
影响因子：
12.4
通讯作者：
Hung, C. -H.
中科院分区：
文献类型：
--
作者：
Kuo, C. -H.;Hsieh, C. -C.;Hung, C. -H.
背景暴露于环境内分泌干扰物（EDCs）与变态反应、慢性炎症和免疫缺陷有关。邻苯二甲酸酯是塑料工业中常用的内分泌干扰物，可作为佐剂破坏免疫系统并增强过敏反应。浆细胞样树突状细胞（Plasmacytoid DCs，pDC）是分泌I型干扰素（type I interferon，IFN）抗感染的优势细胞，也是调节获得性免疫的专职抗原提呈细胞。然而，邻苯二甲酸酯对pDCs的功能的影响是unknown.MethodsCirculating pDCs分离自健康受试者，用邻苯二甲酸二乙基己酯（DEHP）和邻苯二甲酸丁基苄基酯（BBP）进行预处理，并用Toll样受体（TLR）-9激动剂CpG进行刺激。使用ELISA、流式细胞术和pDC/T细胞共培养试验研究IFN-/IFN-水平、表面标志物和T细胞刺激功能。机制进行了研究，使用受体拮抗剂，通路抑制剂，蛋白质印迹法，染色质免疫沉淀。ResultsDiethylhexyl phthalate和丁基苄基邻苯二甲酸酯抑制CpG诱导的IFN-/IFN-表达的pDCs，和效果逆转芳烃受体（AHR）拮抗剂。邻苯二甲酸二乙基己酯抑制CpG激活的丝裂原活化蛋白激酶（MAPK）-MEK 1/2-ERK-ELK 1和NFB信号通路。邻苯二甲酸二乙基己酯通过抑制H3 K4特异性三甲基转移酶WDR 5从细胞质向细胞核的转位，抑制组蛋白H3 K4在IRF 7基因启动子区的三甲基化，从而抑制CpG诱导的IRF 7表达。邻苯二甲酸丁基苄酯或邻苯二甲酸二乙基己酯处理的pDCs抑制IFN-，但增强IL-13的产生由CD 4 + T cells.ConclusionPhthalates可能干扰抗感染的免疫和促进Th 2反应的偏移，增加过敏作用于人pDCs通过抑制IFN-/IFN-的表达和调节的能力，刺激T细胞反应。
BackgroundExposure to environmental endocrine-disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen-presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown.MethodsCirculating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll-like receptor (TLR)-9 agonist CpG. IFN-/IFN- levels, surface markers, and T-cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T-cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation.ResultsDiethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-/IFN- expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG-activated mitogen-activated protein kinase (MAPK)-MEK1/2-ERK-ELK1 and NFB signaling pathways. Diethylhexyl phthalate suppressed CpG-induced interferon regulatory factor (IRF)-7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4-specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate-treated pDCs suppressed IFN- but enhanced IL-13 production by CD4+ T cells.ConclusionPhthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-/IFN- expression and modulating the ability to stimulate T-cell responses.