Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation
Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation
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DOI：
10.1002/eji.200535140
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发表时间：
2006-05-01
影响因子：
5.4
通讯作者：
Kuribayashi, K
中科院分区：
文献类型：
--
作者：
Kato, T;Tada-Oikawa, S;Kuribayashi, K
内分泌干扰物（EDC）广泛存在于环境中，对人体健康可能产生多种不良影响。在本研究中，我们已经表明，一些EDC [二苯甲酮，对辛基苯酚和三丁基氯化锡（TBT）]通过抑制和增强Th 1和Th 2的发展，分别促进强Th 2极化，从幼稚的CD 4（+）T细胞与抗CD 3和脾抗原呈递细胞（APC）启动。研究表明，这种作用是间接的，通过抑制APC的IL-12产生和增加IL-10产生，这分别对Th 1和Th 2的发育至关重要。EDC对细胞因子产生的这种调节与APC细胞内谷胱甘肽水平的降低有关。IL-10剥夺或N-乙酰半胱氨酸的加入，在引发过程中降低细胞内谷胱甘肽水平，取消EDC对促进Th 2极化的作用。口服TBT，最有效地促进Th 2极化在体外，加剧了过敏性哮喘的小鼠模型的气道炎症，伴随着Th 2型免疫增强。总的来说，这些结果表明，EDC，如二苯甲酮，对辛基苯酚，和TBT促进Th 2极化间接通过耗尽谷胱甘肽在APC和随后的调制IL-10和IL-12的生产，可能会导致过敏性疾病的恶化。
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.