Role of Nrf2 in immunotoxicity by food additives and environmental contaminants

描述（由申请人提供） 最近的研究表明，核因子红细胞2相关因子2（Nrf 2）在对抗氧化和亲电细胞应激中起着关键的细胞保护作用。nrf 2被多种化学物质激活，包括环境污染物，如砷、镉、镍、香烟烟雾和柴油机尾气，以及工业副产品，如N-乙基半胱氨酸。此外，几种广泛使用的食品防腐剂也会强烈激活Nrf 2。 因此，Nrf 2激活剂在环境和我们的食物中广泛传播。最近发表的几篇论文描述了Nrf 2在先天免疫中的抑制作用。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在获得性免疫中也起着重要作用，但迄今为止还没有研究Nrf 2在淋巴细胞中的作用。初步数据表明，活化的Nrf 2抑制活化的T细胞中的IFN γ产生。由于IFN γ是巨噬细胞和T细胞的关键活化剂，因此IFN γ被认为是细胞介导的适应性免疫应答（例如对细菌病原体的应答）的重要细胞因子。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产生的机制。这将通过1）确定Nrf 2的激活抑制IFN γ转录的机制2）确定tBHQ（Nrf 2激活剂）损害体内免疫应答的机制和3）确定人Keap 1基因（Nrf 2阻遏物）中的多态性和其他变异对T细胞功能的影响来实现。 由于许多环境污染物，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。这对于免疫系统特别相关，其中Nrf 2对适应性免疫的作用在很大程度上是未表征的。 此外，还应考虑多种Nrf 2激活剂的长期和/或累积暴露。这些研究的总体目的是确定Nrf 2损害T细胞功能的机制，以便更好地预测急性和长期暴露于Nrf 2激活剂对人体免疫系统的影响。 公共卫生相关性：几种食品防腐剂（tBHQ、BHA等）和环境污染物（镉、砷等）激活Nrf 2，一种在大多数细胞类型中发现的蛋白质。 初步研究表明，Nrf 2的激活对T细胞功能有负面影响，导致免疫应答受损。拟议的研究将研究这是如何发生的，以便更好地预测Nrf 2激活剂对免疫系统的影响。

DESCRIPTION (provided by applicant) 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. 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. Public Health Relevance: Several food preservatives (tBHQ, BHA, etc.) and environmental contaminants (cadmium, arsenic, etc.) activate Nrf2, a protein found in most cell types. Preliminary studies demonstrate that activation of Nrf2 has a negative impact on T cell function which leads to impaired immune responses. The proposed studies will examine how this occurs in order to better predict the impact of Nrf2 activators on the immune system.