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，核因子红系2相关因子2(NRF2)在对抗细胞氧化和亲电应激中发挥着重要的细胞保护作用。NRF2被各种化学物质激活，包括环境污染物，如砷、镉、镍、香烟烟雾和柴油废气，以及工业副产品，如四氟乙基半胱氨酸。此外，几种广泛使用的食品防腐剂也强烈激活了Nrf2。因此，Nrf2激活剂广泛分布在环境和我们的食物中。最近发表了几篇论文，描述了Nrf2在先天性免疫中的抑制作用。此外，在Nrf2基因缺失的小鼠中，狼疮样病理的发展表明Nrf2在获得性免疫中也发挥着重要作用，但迄今为止还没有关于Nrf2在淋巴细胞中的作用的研究发表。初步数据表明，激活的Nrf2抑制激活的T细胞产生干扰素-γ。由于干扰素是巨噬细胞和T细胞的关键激活剂，干扰素被认为是细胞介导的适应性免疫反应(如对细菌病原体的反应)的重要细胞因子。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的机制。这将通过1)确定Nrf2激活抑制干扰素伽玛转录的机制2)确定Nrf2激活剂TBHQ在体内损害免疫反应的机制以及3)确定人类Keap1基因(Nrf2抑制物)的多态和其他变异对T细胞功能的影响。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可以激活Nrf2，因此需要充分表征Nrf2激活对不同器官系统的影响。这与免疫系统尤其相关，在免疫系统中，Nrf2对获得性免疫的影响在很大程度上尚未确定。此外，还应考虑大量NRF2激活剂的长期和/或累积暴露。这些研究的总体目的是确定Nrf2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Nrf2激活剂对人类免疫系统的影响。 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Nrf2，这是一种存在于大多数细胞类型中的蛋白质。初步研究表明，Nrf2的激活对T细胞功能有负面影响，从而导致免疫反应受损。拟议的研究将研究这种情况是如何发生的，以便更好地预测Nrf2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.