Role of Nrf2 in immunotoxicity by food additives and environmental contaminants

最近的研究表明，核因子红系2相关因子2(NRF2)在细胞保护中起重要作用 在对抗氧化和亲电细胞压力方面的作用。NRF2被各种化学物质激活， 包括砷，镉，镍，香烟烟，柴油尾气等环境污染物， 以及工业副产品，如四氟乙基半胱氨酸。此外，几种广泛使用的食物 防腐剂也能强烈激活Nrf2。因此，NRF2激活剂在环境中广泛传播 在我们的食物中。最近发表的几篇论文描述了Nrf2在体内的抑制作用 先天免疫力。此外，Nrf2基因缺失小鼠狼疮样病理的发展表明，Nrf2还 在获得性免疫中起着重要作用，但目前还没有研究检测Nrf2在淋巴细胞中的作用 到目前为止已经出版了。我们的初步数据显示，激活的Nrf2抑制干扰素-γ的产生 在激活的T细胞中。因为干扰素是巨噬细胞和T细胞的关键激活剂，所以干扰素是 被认为是细胞介导的适应性免疫反应(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 NRF2抑制T细胞产生干扰素-γ。这将通过1)通过以下方式确定机制来实现 Nrf2的哪种激活抑制了干扰素γ转录2)确定了TBHQ，一种Nrf2 激活剂，损害体内的免疫反应，以及3)确定多态和其他因素的影响 人类Keap1基因(Nrf2抑制物)对T细胞功能的影响。因为无数的环境 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Nrf2，需要充分研究Nrf2激活对不同器官系统的影响。这是 Nrf2对获得性免疫的影响在很大程度上与免疫系统有关 没有特征的。此外，许多NRF2激活剂的长期和/或累积暴露也应 会被考虑。这些研究的总体目的是确定Nrf2损害T细胞的机制 为了更好地预测急性和长期暴露于Nrf2激活剂对细胞功能的影响 人类的免疫系统。

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.