Importance of AhR for the cellular function and communication of dendritic cells

AhR 对树突状细胞的细胞功能和通讯的重要性

• 批准号: 8239472
• 负责人: CHRISTOPH F A VOGEL
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239472
• 关键词: ARNT gene; Address; Affect; Amino Acids; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Biological; Biological Process; Bone Marrow; CCR6 gene; COS Cells; Cell Differentiation process; Cell Nucleus; Cell model; Cell physiology; Cells; Communication; Confocal Microscopy; Critical Pathways; Data; Deletion Mutation; Dendritic Cells; Dendritic cell activation; Development; Dioxins; Disease; Energy Transfer; Exposure to; Gene Targeting; Genetic; Goals; Health; Human; Human Cell Line; Hypersensitivity; Immune System Diseases; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; In Vitro; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-17; Lead; Ligands; Link; Liver; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; NF-kappa B; Natural Immunity; Pathway interactions; Play; Population; Predisposition; Prevention therapy; Proliferation Marker; Proteins; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Spleen; Stimulus; Surface; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Tetrachlorodibenzodioxin; Toxic Environmental Substances; Tryptophan; Work; aryl hydrocarbon receptor ligand; base; chemokine; chromatin immunoprecipitation; insight; interleukin-22; member; mouse model; new therapeutic target; novel; pollutant; transcription factor

DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify the regulatory role of the aryl hydrocarbon receptor (AhR) interacting with NF-?B signaling in controlling function and differentiation of dendritic cells (DC). Alteration of cellular communication of DC with T cells can lead to immunological disorders like autoimmune diseases, allergy and immunodeficiency. Especially interaction of the AhR with NF-?B RelB mediated pathways critical for appropriate immune responses will be the focus of this study. DCs are key regulator of immunity or tolerance, and the NF-?B members RelA and RelB are critical for the development, differentiation and function of DC. Therefore, the AhR may interact with NF-?B Rel proteins to regulate the function of DCs, which affects T cell differentiation in particular pathological conditions mediated by activation of NF-?B and AhR. This study can provide a definite link and mechanism between the exposure to persistent organic pollutants like dioxin and dioxin-like compounds activating the AhR and the development of diseases based on their immunotoxic effects. This will allow for more clearly defined endpoints to assess the effects of AhR activating compounds and may also provide opportunities to develop new substances that can then be used to manipulate the immune system and allow for effective preventative measures to be implemented. PUBLIC HEALTH RELEVANCE: The present study focuses on a novel concept of the function of aryl hydrocarbon receptor (AhR) in cross-talk with NF-?B signaling pathways important for the understanding how the transcriptional potential and activity of the AhR is implemented in the differentiation and function of dendritic cells in the immune system. The current study is critical in understanding the potential biological function of the AhR in the immune system and its role in immunological disorders like allergy or autoimmune disease. This work will help to understand the mechanism how environmental toxicants like dioxin or dioxin-like compounds, which activate the AhR, affect critical functions of the immune system and human health.

描述（由申请人提供）：该提案的总体目标是确定芳烃受体（AhR）与 NF-κB 信号传导相互作用在控制树突细胞（DC）功能和分化中的调节作用。 DC 与 T 细胞的细胞通讯的改变可能导致免疫性疾病，如自身免疫性疾病、过敏和免疫缺陷。特别是 AhR 与 NF-κB RelB 介导的途径的相互作用对于适当的免疫反应至关重要，将是本研究的重点。 DCs是免疫或耐受的关键调节因子，NF-κB成员RelA和RelB对于DC的发育、分化和功能至关重要。因此，AhR可能与NF-κB Rel蛋白相互作用来调节DC的功能，从而在NF-κB和AhR激活介导的特定病理条件下影响T细胞分化。这项研究可以提供持久性有机污染物（如二恶英和二恶英类化合物激活 AhR）与基于其免疫毒性作用的疾病发展之间的明确联系和机制。这将允许更明确定义的终点来评估 AhR 激活化合物的作用，并且还可能提供开发新物质的机会，这些新物质随后可用于操纵免疫系统并允许实施有效的预防措施。 公共健康相关性：本研究重点关注芳烃受体 (AhR) 在与 NF-κB 信号通路串扰中的功能的新概念，对于理解 AhR 的转录潜力和活性如何在免疫系统中树突状细胞的分化和功能中发挥重要作用。目前的研究对于了解 AhR 在免疫系统中的潜在生物学功能及其在过敏或自身免疫性疾病等免疫性疾病中的作用至关重要。这项工作将有助于了解二恶英或二恶英类化合物等环境毒物如何激活 AhR，影响免疫系统和人类健康的关键功能。