Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells.

Chih Hsing Hung, San Nan Yang, Ya Fang Wang, Wei Ting Liao, Po Lin Kuo, Eing Mei Tsai, Chin Lai Lee, Yu Shen Chao, Hsin Su Yu, Shau Ku Huang, Jau Ling Suen

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Abstract

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. 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. 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. 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. 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.

Original languageEnglish
JournalPLoS One
Volume8
Issue number9
DOIs
Publication statusPublished - Jan 1 2013

Fingerprint

dendritic cells
Dendritic Cells
cytokines
histones
Cytokines
interleukin-10
Histones
inflammation
lungs
Interleukin-10
Enterovirus
endocrine-disrupting chemicals
elks
mice
mononuclear leukocytes
epigenetics
Pneumonia
estrogens
Histone Code
immune system

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Hung, C. H., Yang, S. N., Wang, Y. F., Liao, W. T., Kuo, P. L., Tsai, E. M., ... Suen, J. L. (2013). Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells. PLoS One, 8(9). https://doi.org/10.1371/journal.pone.0073534

Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells. / Hung, Chih Hsing; Yang, San Nan; Wang, Ya Fang; Liao, Wei Ting; Kuo, Po Lin; Tsai, Eing Mei; Lee, Chin Lai; Chao, Yu Shen; Yu, Hsin Su; Huang, Shau Ku; Suen, Jau Ling.

In: PLoS One, Vol. 8, No. 9, 01.01.2013.

Research output: Contribution to journalArticle

Hung, CH, Yang, SN, Wang, YF, Liao, WT, Kuo, PL, Tsai, EM, Lee, CL, Chao, YS, Yu, HS, Huang, SK & Suen, JL 2013, 'Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells.', PLoS One, vol. 8, no. 9. https://doi.org/10.1371/journal.pone.0073534
Hung, Chih Hsing ; Yang, San Nan ; Wang, Ya Fang ; Liao, Wei Ting ; Kuo, Po Lin ; Tsai, Eing Mei ; Lee, Chin Lai ; Chao, Yu Shen ; Yu, Hsin Su ; Huang, Shau Ku ; Suen, Jau Ling. / Environmental alkylphenols modulate cytokine expression in plasmacytoid dendritic cells. In: PLoS One. 2013 ; Vol. 8, No. 9.
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abstract = "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. 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. 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. 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. 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.",
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