Modulation of cytokine expression in human myeloid dendritic cells by environmental endocrine-disrupting chemicals involves epigenetic regulation

Chih Hsing Hung, San Nan Yang, Po Lin Kuo, Yu Te Chu, Hui Wen Chang, Wan Ju Wei, Shau Ku Huang, Yuh Jyh Jong

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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-α (TNF-α) but decreased baseline and lipopolysaccharide (LPS)-induced (interleukin) (IL)-10 production; the increase in TNF-α was partially reversible by an estrogen receptor (ER) antagonist. Activation of the MKK3/6-p38 signaling pathway marked the effect of NP on TNF-α 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-α 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-γ. 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.

Original languageEnglish (US)
Pages (from-to)67-72
Number of pages6
JournalEnvironmental health perspectives
Issue number1
StatePublished - Jan 2010
Externally publishedYes


  • Dendritic cell
  • Endocrine-disrupting chemical
  • Epigenetic
  • MLL
  • Mixed-lineage leukemia
  • Nonylphenol

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis


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