Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Environ Health Perspect. 2010 Jan;118(1):67-72. doi: 10.1289/ehp.0901011.
Exposure to environmental endocrine-disrupting chemicals (EDCs) is often associated with dysregulated immune homeostasis, but the mechanisms of action remain unclear.
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.
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.
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.
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.
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。
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。
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。
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。
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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