环境内分泌干扰物通过表观遗传调控调节人髓样树突状细胞细胞因子的表达。
Modulation of cytokine expression in human myeloid dendritic cells by environmental endocrine-disrupting chemicals involves epigenetic regulation.
机构信息
Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
出版信息
Environ Health Perspect. 2010 Jan;118(1):67-72. doi: 10.1289/ehp.0901011.
BACKGROUND
Exposure to environmental endocrine-disrupting chemicals (EDCs) is often associated with dysregulated immune homeostasis, but the mechanisms of action remain unclear.
OBJECTIVES
The aim of this study was to test a hypothesis that EDCs regulate the functions of human dendritic cells, a front-line, immunoregulatory cell type in contact with the environment.
METHODS
We investigated circulating myeloid dendritic cells (mDCs) from five subjects and measured their responses, with or without coculture with autologous T cells, to two common EDCs, nonylphenol (NP) and 4-octylphenol (4-OP). EDC-associated cytokine responses, signaling events, and histone modifications were examined using ELISA, Western blotting, and chromatin immunoprecipitation (ChIP) assays, respectively.
RESULTS
In all cases, mDCs treated with NP or 4-OP demonstrated increased expression of tumor necrosis factor-alpha (TNF-alpha) but decreased baseline and lipopolysaccharide (LPS)-induced (interleukin) (IL)-10 production; the increase in TNF-alpha was partially reversible by an estrogen receptor (ER) antagonist. Activation of the MKK3/6-p38 signaling pathway marked the effect of NP on TNF-alpha expression, concomitant with enhanced levels of methyltranferase complex [mixed-lineage leukemia (MLL) and tryptophan-aspartic acid repeat domain 5 (WDR5)] in the nucleus and of trimethylated H3K4, acetylated H3, and H4 at the TNFA gene locus. Further, up-regulated TNF-alpha expression was significantly suppressed in NP-treated mDCs by a histone acetyltransferase inhibitor. In the presence of NP-treated mDCs, T cells showed increased levels of IL-13 but decreased expression of interferon-gamma.
CONCLUSIONS
These results suggest that NP and 4-OP may have functional effects on the response of mDCs via, in part, the ER, MKK3/6-p38 MAPK signaling pathway, and histone modifications, with subsequent influence on the T-cell cytokine responses.
背景
接触环境内分泌干扰化学物质（EDCs）通常与免疫稳态失调有关，但作用机制尚不清楚。
目的
本研究旨在验证一个假设，即 EDC 调节人类树突状细胞的功能，树突状细胞是与环境接触的一线免疫调节细胞类型。
方法
我们研究了来自五个供体的循环髓样树突状细胞（mDC），并测量了它们的反应，包括与自体 T 细胞共培养或不共培养的反应，以两种常见的 EDC，壬基酚（NP）和 4-辛基酚（4-OP）。使用 ELISA、Western blot 和染色质免疫沉淀（ChIP）测定分别检查 EDC 相关细胞因子反应、信号事件和组蛋白修饰。
结果
在所有情况下，用 NP 或 4-OP 处理的 mDC 均表现出肿瘤坏死因子-α（TNF-α）表达增加，但基础和脂多糖（LPS）诱导的（白细胞介素）（IL）-10 产生减少；雌激素受体（ER）拮抗剂部分逆转了 TNF-α 的增加。MKK3/6-p38 信号通路的激活标志着 NP 对 TNF-α表达的影响，同时伴随着核内甲基转移酶复合物[混合谱系白血病（MLL）和色氨酸-天冬氨酸重复域 5（WDR5）]水平升高，以及 TNFA 基因座上三甲基化 H3K4、乙酰化 H3 和 H4 水平升高。此外，NP 处理的 mDC 中组蛋白乙酰转移酶抑制剂显著抑制了上调的 TNF-α 表达。在 NP 处理的 mDC 存在的情况下，T 细胞表现出 IL-13 水平升高，但干扰素-γ表达降低。
结论
这些结果表明，NP 和 4-OP 可能通过部分 ER、MKK3/6-p38 MAPK 信号通路和组蛋白修饰对 mDC 的反应产生功能影响，进而对 T 细胞细胞因子反应产生影响。
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