Modulation of cytokine expression in human myeloid dendritic cells by environmental endocrine-disrupting chemicals involves epigenetic regulation.
BACKGROUND
Exposure to environmental endocrine-disrupting chemicals (EDCs) is often associated with dysregulated immune homeostasis, but the mechanisms of action remain unclear.


OBJECTIVE
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.
Hung
Chih-Hsing
CH
Department of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yang
San-Nan
SN
Kuo
Po-Lin
PL
Chu
Yu-Te
YT
Chang
Hui-Wen
HW
Wei
Wan-Ju
WJ
Huang
Shau-Ku
SK
Jong
Yuh-Jyh
YJ
D000328:Adult; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D052244:Endocrine Disruptors / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018793:Interleukin-13 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010636:Phenols / Q000633:toxicity; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D055815:Young Adult
D016207:Cytokines; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D006657:Histones; C508609:IL10 protein, human; D018793:Interleukin-13; D010636:Phenols; D011960:Receptors, Estrogen; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C025256:nonylphenol; C080417:4-octylphenol; D007371:Interferon-gamma