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

• 批准号: 8385694
• 负责人: Cheryl Elizabeth Rockwell
• 金额: $ 24.9万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-16 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385694
• 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; response; sensor; transcription factor

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.

最近的研究表明，核因子红细胞 2 相关因子 2 (Nrf2) 发挥着关键的细胞保护作用。 对抗氧化和亲电子细胞应激的作用。 Nrf2 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， 以及工业副产品，例如四氟乙基半胱氨酸。此外，还有几种广泛使用的食品 防腐剂也会强烈激活 Nrf2。因此，Nrf2激活剂在环境中广泛传播 以及我们的食物中。最近发表的几篇论文描述了 Nrf2 在 先天免疫。此外，Nrf2缺失小鼠中狼疮样病理的发展表明Nrf2也 在适应性免疫中发挥重要作用，但尚无研究检查 Nrf2 在淋巴细胞中的作用 迄今为止已发布。我们的初步数据表明，激活的 Nrf2 抑制 IFN γ 的产生 在活化的T细胞中。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（例如对细菌的反应）的重要细胞因子 病原）。本申请中提出的研究的目的是确定其机制 Nrf2 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 Nrf2 的激活会抑制 IFN gamma 转录 2) 确定 tBHQ（Nrf2 的一种）的机制 激活剂，损害体内免疫反应，3) 确定多态性和其他的影响 人类 Keap1 基因（Nrf2 阻遏蛋白）的变异对 T 细胞功能的影响。由于众多环保 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，需要充分表征 Nrf2 激活对不同器官系统的影响。这是 与免疫系统特别相关，其中 Nrf2 对适应性免疫的影响很大程度上是 没有特征的。此外，大量 Nrf2 激活剂的长期和/或累积暴露也应 予以考虑。这些研究的总体目的是确定 Nrf2 损害 T 的机制 细胞功能，以便更好地预测急性和长期暴露于 Nrf2 激活剂对细胞的影响 人类的免疫系统。