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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：
7872631
负责人：
Cheryl Elizabeth Rockwell
金额：
$ 8.72万
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 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7872631
关键词：
2-tert-butylhydroquinone Acute Affect Antibody Formation Antigens Arsenic Cadmium Cell Nucleus Cell physiology Cells Cellular Stress Chemicals Computer Systems Development 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 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 systems research 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）