Role of Aryl hydrocarbon receptor (AhR) and RelB during the initiation of dendrit

芳烃受体 (AhR) 和 RelB 在树突形成过程中的作用

• 批准号: 7895003
• 负责人: CHRISTOPH F A VOGEL
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895003
• 关键词: ARNT protein; Affect; Agonist; Aryl Hydrocarbon Receptor; Binding; Biological; Biological Assay; Bone Marrow; Bone Marrow Cells; CD80 gene; Cell Differentiation process; Cell Line; Cell Nucleus; Cells; Complex; Confocal Microscopy; Dendritic Cells; Dioxins; EMSA; Elements; Enzymes; Family; Flow Cytometry; Gene Expression; Gene Silencing; Genetic Transcription; Goals; Health; Human; IL8 gene; Image; Immune; Immune response; Immune system; In Vitro; Interleukin-8; Investigation; Knowledge; Ligands; Luciferases; Measurement; Mediating; Modeling; Mus; Myeloid Cells; Nuclear Protein; Nuclear Proteins; Pathway interactions; Physiological; Play; Process; Receptor Signaling; Regulation; Regulator Genes; Reporter; Research; Role; Signal Pathway; Source; Spleen; Surface; System; T-Lymphocyte; TNFRSF5 gene; Testing; Tetrachlorodibenzodioxin; Time; Toxic Environmental Substances; Toxic effect; Work; Xenobiotics; aryl hydrocarbon receptor ligand; base; chemokine; cytokine; dimer; in vivo; insight; lead immunotoxic effect; mRNA Expression; member; mouse Ahr protein; novel; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): This proposal investigates a new mechanism of cross talk between the transcription factors Aryl hydrocarbon Receptor (AhR) and the NF-?B member RelB in the process of dendritic cell (DC) differentiation. The long-term objective of the project is to give insight into the missing knowledge about the endogenous role of the AhR and its role together with RelB in regulating gene transcription especially immune regulatory genes like cytokines and chemokines. The major impetus for this study has been provided by recent findings that RelB, a member of the NF-?B family, may play an important role in the classical AhR signaling pathway. In the present study, we will assess the physiological relevance of the AhR/RelB activity in human DC in vitro systems for the process of DC differentiation. We like to evaluate the established human myeloid cell lines U937 and THP-1 as a source of DC-like cells since most if not all studies with DC and dioxin have been performed in mice or cells derived from mouse. Further, we like to test the effect of TCDD (AhR agonist) and AhR antagonists on differentiation and the biological response of the DCs based on the measurement of selected activation markers such as surface expression of CD1a, CD40, CD80, CD86 and MHCII by flow cytometry and chemokines relevant for the function of DCs like DC-CK1, DC-STAMP, and IL-8 mRNA expression by real time PCR analysis. In project 2 of the current proposal we will identify the role of AhR and AhR/RelB activity in the differentiation process of bone marrow cells derived from C57BL/6 wild type and AhR null (AhR-/-) mice into DC. This study reveals a novel concept of the function of the AhR together with RelB and is critical in understanding how environmental toxicants like dioxins affect critical functions of the immune system and human health. PUBLIC HEALTH RELEVANCE: About 15 years ago Hankinson and coworkers identified the encoded protein ARNT, which is required for ligand-dependent translocation of the Aryl hydrocarbon Receptor (AhR) to the nucleus and its binding to Dioxin responsive elements (DRE) mediating induction of xenobiotic metabolizing enzymes (classical AhR/ARNT pathway), but the physiological role of the AhR remains a key question. The present study focuses on a new mechanism of cross talk between AhR and the NF- ?B member RelB (alternative AhR/RelB pathway), which suggests an example of how an activated AhR pathway may connect to the NF-?B subunit RelB in order to cooperatively regulate cytokine/chemokine expression as well as differentiation and function of dendritic cells. This work will help to understand the mechanism how environmental toxicants like dioxin or dioxin-like compounds, which activate the AhR, elicit immunotoxic effects and lead to adverse health effects.

描述（申请人提供）：该提案研究了树突状细胞（DC）分化过程中转录因子芳基烃受体（AhR）与NF-κB成员RelB之间串扰的新机制。该项目的长期目标是深入了解有关 AhR 的内源性作用及其与 RelB 一起调节基因转录尤其是细胞因子和趋化因子等免疫调节基因的作用的知识。最近的研究结果为这项研究提供了主要动力，即 NF-κB 家族成员 RelB 可能在经典 AhR 信号通路中发挥重要作用。在本研究中，我们将评估人 DC 体外系统中 AhR/RelB 活性与 DC 分化过程的生理相关性。我们喜欢评估已建立的人类骨髓细胞系 U937 和 THP-1 作为 DC 样细胞的来源，因为大多数（如果不是全部）DC 和二恶英研究都是在小鼠或小鼠来源的细胞中进行的。此外，我们希望通过流式细胞术测量选定的激活标记物（例如 CD1a、CD40、CD80、CD86 和 MHCII 的表面表达）来测试 TCDD（AhR 激动剂）和 AhR 拮抗剂对 DC 分化和生物反应的影响通过实时 PCR 分析与 DC 功能相关的细胞计数和趋化因子，如 DC-CK1、DC-STAMP 和 IL-8 mRNA 表达。在当前提案的项目 2 中，我们将确定 AhR 和 AhR/RelB 活性在源自 C57BL/6 野生型和 AhR null (AhR-/-) 小鼠的骨髓细胞分化为 DC 的过程中的作用。这项研究揭示了 AhR 与 RelB 的功能的新概念，对于理解二恶英等环境毒物如何影响免疫系统和人类健康的关键功能至关重要。公共健康相关性：大约 15 年前，Hankinson 及其同事发现了编码蛋白 ARNT，该蛋白是配体依赖性芳基碳氢化合物受体 (AhR) 易位至细胞核及其与二恶英反应元件 (DRE) 结合所必需的，介导异生物质的诱导代谢酶（经典 AhR/ARNT 途径），但 AhR 的生理作用仍然是一个关键问题。本研究重点关注 AhR 和 NF-κB 成员 RelB（替代 AhR/RelB 途径）之间的新串扰机制，这提出了一个激活的 AhR 途径如何与 NF-κB 亚基 RelB 连接的示例。以协同调节细胞因子/趋化因子的表达以及树突状细胞的分化和功能。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、引发免疫毒性作用并导致不良健康影响的机制。

项目成果

AhR deficiency impairs expression of LPS-induced inflammatory genes in mice.

AhR 缺陷会损害小鼠体内 LPS 诱导的炎症基因的表达。

• DOI: 10.1016/j.bbrc.2011.06.018
• 发表时间: 2011
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Wu,Dalei;Li,Wen;Lok,Patty;Matsumura,Fumio;Vogel,ChristophFranzAdam
• 通讯作者: Vogel,ChristophFranzAdam

Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice.

• DOI: 10.1161/atvbaha.110.220202
• 发表时间: 2011-06
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Wu D;Nishimura N;Kuo V;Fiehn O;Shahbaz S;Van Winkle L;Matsumura F;Vogel CF
• 通讯作者: Vogel CF

Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression.

• DOI: 10.1016/j.abb.2011.05.011
• 发表时间: 2011-08-01
• 期刊: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
• 影响因子: 3.9
• 作者: Vogel, Christoph Franz Adam;Li, Wen;Wu, Dalei;Miller, Jamie K.;Sweeney, Colleen;Lazennec, Gwendal;Fujisawa, Yasuko;Matsumura, Fumio
• 通讯作者: Matsumura, Fumio