title: Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation.
abstract: BACKGROUND
  Exposure 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.
  
  
  METHODS
  Circulating 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-α/IFN-β 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.
  
  
  RESULTS
  Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-α/IFN-β 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 NFκB 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-γ but enhanced IL-13 production by CD4+ T cells.
  
  
  CONCLUSIONS
  Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-α/IFN-β expression and modulating the ability to stimulate T-cell responses.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Kuo
authors.forename: C-C
authors.initials: CC
authors.lastname: Hsieh
authors.forename: H-F
authors.initials: HF
authors.lastname: Kuo
authors.forename: M-Y
authors.initials: MY
authors.lastname: Huang
authors.forename: S-N
authors.initials: SN
authors.lastname: Yang
authors.forename: L-C
authors.initials: LC
authors.lastname: Chen
authors.forename: S-K
authors.initials: SK
authors.lastname: Huang
authors.forename: C-H
authors.initials: CH
authors.lastname: Hung
mesh_terms: D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D057890:Epigenomics; D005434:Flow Cytometry; D006801:Humans; D007370:Interferon Type I / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000032:analysis / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D010795:Phthalic Acids; D051217:Toll-Like Receptor 9; C032279:phthalic acid; D016899:Interferon-beta; D007371:Interferon-gamma; C027561:butylbenzyl phthalate
keywords: dendritic cell; endocrine-disrupting chemical; epigenetics; interferon; phthalate