Role of Nrf2 in immunotoxicity by food additives and environmental contaminants

最近的研究表明，核因子红细胞2相关因子2（Nrf 2）在细胞凋亡中起着重要的细胞保护作用。 在对抗氧化和亲电子细胞应激中的作用。nrf 2被多种化学物质激活， 包括环境污染物如砷、镉、镍、香烟烟雾和柴油机废气， 以及工业副产物如N-乙基半胱氨酸。此外，几种广泛使用的食物 防腐剂也强烈激活Nrf 2。因此，Nrf 2激活剂在环境中广泛传播 在我们的食物中。最近发表了几篇论文，描述了Nrf 2在肿瘤中的抑制作用。 先天免疫此外，在Nrf 2基因敲除小鼠中狼疮样病理学的发展表明，Nrf 2也 在获得性免疫中起重要作用，但没有研究检查Nrf 2在淋巴细胞中的作用， 至今已出版。我们的初步数据表明，激活的Nrf 2抑制IFN γ的产生， 活化的T细胞因为IFN γ是巨噬细胞和T细胞的关键激活剂， 被认为是细胞介导的适应性免疫反应（例如对细菌的反应）的重要细胞因子 病原体）。本申请中提出的研究的目的是确定 Nrf 2抑制T细胞中IFN γ的产生。这将通过以下方式实现：1）确定机制， 其中Nrf 2的激活抑制IFN γ转录2）确定tBHQ，Nrf 2 激活剂，损害体内免疫应答和3）确定多态性和其他 人类Keap 1基因（Nrf 2阻遏物）的变异对T细胞功能的影响。因为许多环境 污染物，工业副产品和常用的合成食品防腐剂已被证明， 激活Nrf 2，Nrf 2激活对不同器官系统的影响需要充分表征。这是 特别是与免疫系统有关，其中Nrf 2对适应性免疫的作用在很大程度上 没有特征的此外，许多Nrf 2激活剂的长期和/或累积暴露也应该 被考虑。这些研究的总体目的是确定Nrf 2损害T细胞的机制。 细胞功能，以便更好地预测急性和长期暴露于Nrf 2激活剂对细胞功能的影响。 人体免疫系统。

Recent studies demonstrate that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical cytoprotective role in countering oxidative and electrophilic cellular stresses. Nrf2 is activated by a variety of chemicals, including environmental contaminants such as arsenic, cadmium, nickel, cigarette smoke, and diesel exhaust, as well as industrial byproducts, such as tetrafluoroethylcysteine. In addition, several widely used food preservatives also strongly activate Nrf2. Thus, Nrf2 activators are widely disseminated in the environment and in our food. Several papers have recently been published describing the suppressive effects of Nrf2 in innate immunity. In addition, the development of lupus-like pathology in Nrf2-null mice suggests that Nrf2 also plays an important role in adaptive immunity, but no studies examining the role of Nrf2 in lymphocytes have been published to date. Our preliminary data demonstrate that activated Nrf2 inhibits IFN gamma production in activated T cells. Because IFN gamma is a key activator of macrophages and T cells, IFN gamma is considered a vital cytokine for cell-mediated adaptive immune responses (such as a response to a bacterial pathogen). The purpose of the studies proposed in this application is to determine the mechanism by which Nrf2 inhibits IFN gamma production in T cells. This will be accomplished by 1) determining the mechanism by which activation of Nrf2 inhibits IFN gamma transcription 2) determining the mechanism by which tBHQ, a Nrf2 activator, impairs immune responses in vivo and 3) determining the effect of polymorphisms and other variations in the human Keap1 gene (Nrf2 repressor) on T cell function. Because numerous environmental contaminants, industrial byproducts, and commonly used synthetic food preservatives have been shown to activate Nrf2, the effects of Nrf2 activation on different organ systems needs to be fully characterized. This is particularly pertinent for the immune system in which the effects of Nrf2 on adaptive immunity are largely uncharacterized. Moreover, the long-term and/or cumulative exposure of numerous Nrf2 activators should also be considered. The overall purpose of these studies is to determine the mechanism by which Nrf2 impairs T cell function in order to better predict the effects of acute and long-term exposure to Nrf2 activators on the immune system in humans.