Exacerbation of airway inflammation by environmental chemicals via suppression of CD4+CD25+ regulatory T cell function

有意或无意地向环境中释放的环境化学品可能对人类健康产生各种不良影响。我们已经表明，环境化学品如二苯甲酮、对辛基苯酚和三丁基氯化锡（TBT）分别通过抑制和增强Th 1和Th 2的发展来促进强Th 2极化，来自用and-CD 3和脾抗原呈递细胞（APC）致敏的初始CD 4 + T细胞。结果表明，该作用是间接的，通过抑制IL-12的产生和增加IL-10的产生，这是关键的Th 1和Th 2的发展，分别。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。TBT在体外能最有效地促进Th 2极化，但在过敏性哮喘小鼠模型中，口服TBT可加重气道炎症，并伴随Th 2型免疫增强。 ...更多信息 环境化学物质作为氧化应激源促进Th 2极化并加重气道炎症。然而，已知氧化应激可促进局部炎症。因此，本研究的第一个目标是研究全身施用环境化学品（1131）和模型氧化应激物（马来酸二甲酯; DEM）促进气道炎症的作用，不是通过促进Th 2极化，而是通过促进kcal氧化应激。我们发现，口服TBT或DEM的剂量，加剧气道炎症减少GBH水平在脾脏，肠系膜淋巴结和外周血单核细胞，但不是肺组织。在暴露于TBT或DEM后转移有OVA特异性Th 2细胞的小鼠在鼻内施用OVA后没有显示增加的气道炎症。此外，来自暴露于TBT或DEM的小鼠的脾APC在体外促进来自初始CD 4 + T细胞的Th 2发育。还已知的是，氧化应激在活化诱导的细胞死亡（AICD）和对AICD的易感性中起关键作用，这在T细胞亚群中是不同的，因此，作为本工作的第二个目标，我们评估了暴露于TBT或DEM的小鼠中CD 4 + CD 25+调节性T细胞对AICD的易感性。用CFSE标记表达OVA特异性TCR的II小鼠，并转移到同类CD 45.1小鼠中，随后用明矾中的OVA免疫并暴露于Tiff或DEM。来自这些小鼠的脾细胞用抗CD45.2、抗Foxp 3和膜联蛋白V染色，其识别转移的CD 4 + T细胞、调节性T细胞、和凋亡细胞中膜磷脂酰丝氨酸外化我们发现，与CD 42 + Foxp 3-细胞中的细胞相比，CD45.2+ Foxp 3 + T细胞中的膜联蛋白V+细胞显著增加。这些结果表明，具有氧化应激活性的环境化学物质通过促进Th 2发育和抑制功能性CD 4 + CD 25+调节性T细胞而使免疫应答偏向Th 2，这导致气道炎症的恶化，而不依赖于促进局部氧化应激。少

Environmental chemicals that are released to the environment by on purpose or accidentally may have various undesirable effects on human health Previously; we have shown that environmental chemicals such as 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 and-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. Oral administrationof 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 Thus, it appears that envi … More ronmental chemicals act as oxidative stressor to promote Th2 polarization and exacerbate airway inflammation. However, oxidative stress is aim known to promote inflammation locally. Therefore, the first goal of the current study was to investigate the effect of systemic administration of environmental chemical (1131) and model oxidative stressor (dimethyl maleate; DEM) promote airway inflammation not via promotion of Th2 polarization, but promotion kcal oxidative stress. We found that oral administration of TBT or DEM at the dose that exacerbate airway inflammation reduced GBH levels in spleen, mesenteric lymph node and peripheral blood mononuclear cells, but not lung tissue. Mice transferred with OVA-specific Th2 calls after exposure of TBT or DEM did not show increased airway inflammation upon intranasal administration of OVA Furthermore, splenic APC from mice exposed TBT or DEM promoted Th2 development from naive CD4+ T cells in vitro. It is also known that oxidative stress critically involved in activation induced cell death (AICD) and susceptibility to AICD differs in T cell subsets, therefore, as the second goal of the present work, we assessed the susceptibility of CD4+CD25+ regulatory T cells to AICD in mice exposed to TBT or DEM. CD4+ T cells containing CD4+CD25+ regulatory T cells and CD4+CD25- T cells from OT-II mice that express-OVA-specific TCR were labeled with CFSE and transferred into congenic CD45.1 mice that subsequently immunized with OVA in alum and exposed to Tiff or DEM. Spleen cells from these mice were stained with anti-CD45.2, anti-Foxp3, and Annexin V, which identifies transferred CD4+ T cells, regulatory T cells, and membrane phophatidylserine externalization in apoptotic cells We found that significant increase in Annexin V+ cells among CD45.2+Foxp3+ T cells as compared to that among CD42+Foxp3- cells Taken altogether, these results indicate that environmental chemicals with oxidative stress activity deviate immune response toward Th2 via promotion of Th2 development and suppression of functional CD4+CD25+ regulatory T cells that resulted in the exacerbation of airway inflammation independently of promoting local oxidative stress. Less