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Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation
Author(s) -
Kuo C.H.,
Hsieh C.C.,
Kuo H.F.,
Huang M.Y.,
Yang S.N.,
Chen L.C.,
Huang S.K.,
Hung C.H.
Publication year - 2013
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12162
Subject(s) - phthalate , aryl hydrocarbon receptor , mapk/erk pathway , biology , interferon , chemistry , immunology , signal transduction , microbiology and biotechnology , transcription factor , gene , biochemistry , organic chemistry
Background Exposure to environmental endocrine‐disrupting chemicals ( EDC s) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDC s used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DC s ( pDC s) 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 pDC s are unknown. Methods Circulating pDC s were isolated from healthy subjects, were pretreated with diethylhexyl phthalate ( DEHP ) and butyl benzyl phthalate ( BBP ), and were stimulated with T oll‐like receptor ( TLR )‐9 agonist C p G . 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 C p G ‐induced IFN ‐α/ IFN ‐β expression in pDC s, and the effect was reversed by aryl hydrocarbon receptor ( AHR ) antagonist. Diethylhexyl phthalate suppressed C p G ‐activated mitogen‐activated protein kinase ( MAPK )‐ MEK 1/2‐ ERK ‐ ELK 1 and NF κ B signaling pathways. Diethylhexyl phthalate suppressed C p G ‐induced interferon regulatory factor ( IRF )‐7 expression by suppressing histone H 3 K 4 trimethylation at IRF 7 gene promoter region through inhibiting translocation of H 3 K 4‐specific trimethyltransferase WDR 5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate‐treated pDC s suppressed IFN ‐γ but enhanced IL‐13 production by CD 4+ T cells. Conclusion Phthalates may interfere with immunity against infection and promote the deviation of T h2 response to increase allergy by acting on human pDC s via suppressing IFN ‐α/ IFN ‐β expression and modulating the ability to stimulate T ‐cell responses.