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

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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