Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation.
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.
Kato
Takuma
T
Department of Bioregulation, Mie University Graduate School of Medicine, Tsu, Mie, Japan. katotaku@doc.medic.mie-u.ac.jp
Tada-Oikawa
Saeko
S
Takahashi
Kazuo
K
Saito
Kanako
K
Wang
Linan
L
Nishio
Akiyoshi
A
Hakamada-Taguchi
Rie
R
Kawanishi
Shosuke
S
Kuribayashi
Kagemasa
K
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
D016207:Cytokines; D052244:Endocrine Disruptors; D016753:Interleukin-10; D005978:Glutathione