Role of Nrf2 in immunotoxicity by food additives and environmental contaminants

Nrf2 在食品添加剂和环境污染物免疫毒性中的作用

基本信息

批准号：
8068037
负责人：
Cheryl Elizabeth Rockwell
金额：
$ 8.92万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068037
关键词：
2-tert-butylhydroquinone Acute Affect Antibody Formation Antigens Arsenic Cadmium Cell Nucleus Cell physiology Cells Cellular Stress Chemicals Cytokine Activation Data Development Diesel Exhaust Drug Metabolic Detoxication Environment Environmental Pollution Enzymes Erythrocytes Exposure to FOS gene Food Food Additives Food Preservatives Future Gene Expression Genes Genetic Polymorphism Genetic Transcription Genetic Variation Glutathione Goals Homeostasis Human Immune Immune response Immune system Immunosuppression Individual Inflammation Influenza Interferon Activation Interferon Suppression Interferon Type II Interferons Knockout Mice Lead Lymphocyte Mediating Molecular Mus Mutation NF-kappa B Natural Immunity Nickel Nuclear Translocation Paper Pathology Pathway interactions Peroxisome Proliferator-Activated Receptors Phosphoric Monoester Hydrolases Play Production Proteins Publishing Repression Research Risk Assessment Role Sheep Signal Pathway Signal Transduction Single Nucleotide Polymorphism Stress Systems Development T-Lymphocyte Testing Transcription Factor AP-1 Tuberculosis Ubiquitination Variant Viral Work Xenobiotics adaptive immunity base body system cell type cigarette smoking cytokine immune function immunotoxicity in vivo lupus-like macrophage novel nuclear factor-erythroid 2 p65 pathogen prevent public health relevance response sensor transcription factor

项目摘要

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.

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 (Nrf2) 在对抗氧化和亲电细胞应激方面发挥着关键的细胞保护作用。 Nrf2 可被多种化学物质激活，包括砷、镉、镍、香烟烟雾和柴油机尾气等环境污染物，以及四氟乙基半胱氨酸等工业副产品。此外，几种广泛使用的食品防腐剂也会强烈激活Nrf2。因此，Nrf2 激活剂在环境和食物中广泛传播。最近发表的几篇论文描述了 Nrf2 在先天免疫中的抑制作用。此外，Nrf2缺失小鼠中狼疮样病理的发展表明Nrf2在适应性免疫中也发挥着重要作用，但迄今为止尚未发表检查Nrf2在淋巴细胞中的作用的研究。初步数据表明，激活的 Nrf2 会抑制激活的 T 细胞中 IFN γ 的产生。由于 IFN γ 是巨噬细胞和 T 细胞的关键激活剂，因此 IFN γ 被认为是细胞介导的适应性免疫反应（例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细胞中IFNγ产生的机制。这将通过以下方式实现：1) 确定 Nrf2 激活抑制 IFN γ 转录的机制 2) 确定 Nrf2 激活剂 tBHQ 损害体内免疫反应的机制 3) 确定多态性和其他变异的影响人类 Keap1 基因（Nrf2 阻遏蛋白）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。这对于免疫系统尤其重要，因为 Nrf2 对适应性免疫的影响在很大程度上是未知的。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。公共健康相关性：多种食品防腐剂（tBHQ、BHA 等）和环境污染物（镉、砷等）会激活 Nrf2（一种存在于大多数细胞类型中的蛋白质）。初步研究表明，Nrf2 的激活会对 T 细胞功能产生负面影响，从而导致免疫反应受损。拟议的研究将研究这是如何发生的，以便更好地预测 Nrf2 激活剂对免疫系统的影响。