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: 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
• 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

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中起关键的细胞保护作用。 NRF2被多种化学物质激活，包括环境污染物，例如砷，镉，镍，香烟烟雾和柴油排气，以及工业副产品，例如四氟甲基半胱氨酸。此外，几种广泛使用的食品防腐剂也强烈激活NRF2。 因此，NRF2激活剂在环境和我们的食物中广泛传播。最近发表了几篇论文，描述了NRF2先天免疫的抑制作用。此外，NRF2-NULL小鼠中类似狼疮的病理的发展表明，NRF2在适应性免疫中也起着重要作用，但是迄今为止尚未发表研究NRF2在淋巴细胞中的作用的研究。初步数据表明，活化的NRF2抑制了活化的T细胞中的IFNγ产生。因为IFN伽玛是巨噬细胞和T细胞的关键激活剂，因此IFN伽马被认为是细胞介导的适应性免疫反应的重要细胞因子（例如对细菌病原体的反应）。本应用中提出的研究的目的是确定NRF2抑制T细胞中IFN伽马产生的机制。这将通过1）确定NRF2激活抑制IFN伽马转录的机制来实现。2）确定NRF2激活剂TBHQ在体内损害免疫反应的机制，并确定人类Keap1 Gene的其他变化的效果（nrf2 propressor）对nrf2 prowsor in nrf2 prouncor t t t t t t t t t t t。 由于已经显示出许多环境污染物，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相关，其中NRF2对适应性免疫的影响在很大程度上没有表征。 此外，还应考虑许多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）激活了大多数细胞类型中发现的蛋白质NRF2。 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。拟议的研究将研究如何发生这种情况，以便更好地预测NRF2激活剂对免疫系统的影响。