title: Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation.
abstract: Endocrine-disrupting chemicals (EDC) are ubiquitous in environment and may have various undesirable effects on human health. In the present study, we have shown that some EDC [benzophenone, p-octylphenol, and tributyltin chloride (TBT)] promoted strong Th2 polarization via suppression and augmentation of Th1 and Th2 development, respectively, from naive CD4+ T cells primed with anti-CD3 and splenic antigen-presenting cells (APC). The effect was indicated to be indirect via suppression of IL-12 production and augmentation of IL-10 production of APC, which are critical for the Th1 and Th2 development, respectively. Such modulation of cytokine production by EDC was associated with reduction of intracellular glutathione levels in APC. IL-10 deprivation or the addition of N-acetylcysteine, which replenishes intracellular glutathione level during priming, cancelled the effect of EDC on the promotion of Th2 polarization. Oral administration of TBT, which most effectively promoted Th2 polarization in vitro, exacerbated airway inflammation in a murine model of allergic asthma with concomitant enhancement of Th2-type immunity. Collectively these results suggest that EDC such as benzophenone, p-octylphenol, and TBT promote Th2 polarization indirectly via the depletion of glutathione in APC and subsequent modulation of IL-10 and IL-12 production that might result in the exacerbation of allergic diseases.
authors.affiliation: Department of Bioregulation, Mie University Graduate School of Medicine, Tsu, Mie, Japan. katotaku@doc.medic.mie-u.ac.jp
authors.forename: Takuma
authors.initials: T
authors.lastname: Kato
authors.forename: Saeko
authors.initials: S
authors.lastname: Tada-Oikawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahashi
authors.forename: Kanako
authors.initials: K
authors.lastname: Saito
authors.forename: Linan
authors.initials: L
authors.lastname: Wang
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishio
authors.forename: Rie
authors.initials: R
authors.lastname: Hakamada-Taguchi
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
authors.forename: Kagemasa
authors.initials: K
authors.lastname: Kuribayashi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000378:metabolism; D001249:Asthma / Q000209:etiology*; D016764:Cell Polarity; D016207:Cytokines / Q000096:biosynthesis; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D016753:Interleukin-10 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000187:drug effects / Q000502:physiology; D018418:Th2 Cells / Q000187:drug effects* / Q000502:physiology
chemical_list: D016207:Cytokines; D052244:Endocrine Disruptors; D016753:Interleukin-10; D005978:Glutathione