title: Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells.
abstract: BACKGROUND
  Alkylphenols, such as nonylphenol (NP) and 4-octylphenol (4-OP), have the potential to disturb immune system due to their weak estrogen-like activity, an effect with potential serious public health impact due to the worldwide distribution of these substances. Plasmacytoid dendritic cells (PDCs) can secrete large amounts of type I IFNs and are critical in immune regulation. However, there has been limited study about the influence of alkylphenols on the function of pDCs.
  
  
  OBJECTIVE
  The aim of this study was to examine the effect of alkylphenols on pDC functions in vitro and in vivo and then further explored the involved signaling pathways and epigenetic changes.
  
  
  METHODS
  Circulating pDCs from human peripheral blood mononuclear cells were treated with alkylphenols with or without CpG stimulation. Alkylphenol-associated cytokine responses, signaling events, histone modifications and viral activity were further examined. In NP-exposed mice, the effect of NP on splenic pDC function and allergic lung inflammation were also assessed.
  
  
  RESULTS
  The results showed that NP increased the expression of TNF-α, but suppressed IL-10 production in the range of physiological doses, concomitant with activation of the MKK3/6-p38 signaling pathway and enhanced levels of acetylated histone 3 as well as histone 4 at the TNFA gene locus. Further, in CpG-stimulated pDCs, NP suppressed type I IFNs production, associated with down-regulation of IRF-7 and MKK1/2-ERK-Elk-1 pathways and led to the impaired anti-enterovirus 71 activity in vitro. Additionally, splenic pDCs from NP-exposed mice showed similar cytokine changes upon CpG stimulation under conditions relevant to route and level of exposure in humans. NP treatment also enhanced allergic lung inflammation in vivo.
  
  
  CONCLUSIONS
  Alkylphenols may influence pDCs' functions via their abilities to induce expression of a pro-inflammatory cytokine, TNF-α, and to suppress regulatory cytokines, including IL-10, IFN-α and IFN-β, suggesting the potential impact of endocrine disrupting chemicals on immune regulation.
authors.affiliation: Department of Pediatrics, Faculty of Pediatrics, Kaohsiung Medical University, Kaohsiung, Taiwan ; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan ; Center of Excellence For Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Hsing
authors.initials: CH
authors.lastname: Hung
authors.forename: San-Nan
authors.initials: SN
authors.lastname: Yang
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Liao
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.forename: Chin-Lai
authors.initials: CL
authors.lastname: Lee
authors.forename: Yu-Shen
authors.initials: YS
authors.lastname: Chao
authors.forename: Hsin-Su
authors.initials: HS
authors.lastname: Yu
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.forename: Jau-Ling
authors.initials: JL
authors.lastname: Suen
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000276:immunology*; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols / Q000008:administration & dosage / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D016898:Interferon-alpha; D010636:Phenols; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016899:Interferon-beta; C025256:nonylphenol; C080417:4-octylphenol
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