IL-2 Suppression by Endocannabinoid Activation of PPARgamma

内源性大麻素激活 PPARgamma 抑制 IL-2

基本信息

批准号：
7254283
负责人：
Norbert E Kaminski
金额：
$ 29.48万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7254283
关键词：
2-arachidonylglycerol 9-deoxy-delta-9-prostaglandin D2 Agonist Attenuated Binding Biological Calcium Cell physiology Cells Coxibs Cultured Cells DNA Binding Data Disruption Elevation Endocannabinoids Enzymes Event Exhibits Functional disorder Gene Expression Goals Homeostasis IL2 gene Immune system Immunologics Interleukin-2 Investigation Kinetics Knockout Mice Leukocytes Ligands Maintenance Mediating Metabolism Molecular NF-AT Nuclear Nuclear Receptors Nuclear Translocation Numbers Other Finding PPAR gamma Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Play Preparation Principal Investigator Prostaglandin-Endoperoxide Synthase Prostaglandins Regulation Research Role Series Signal Transduction Small Interfering RNA Staging System T cell regulation T-Cell Activation T-Lymphocyte Testing anandamide arachidonate attenuation base cannabinoid receptor cyclooxygenase 1 cyclooxygenase 2 insight novel nuclear factors of activated T-cells programs protein protein interaction

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this 5 year research plan is to elucidate the molecular mechanism responsible for the modulation of T cell function and interleukin-2 (IL-2) deregulation by the structurally-related endocannabinoids, anandamide (AEA) and 2-arachidonyl glycerol (2-AG). Presently, the teleological role of the endocannabinoid system is unknown but there is a growing body of evidence suggesting that it may significantly contribute to the maintenance of immunologic homeostasis. Numerous studies have demonstrated profound effects on biological systems by AEA and 2-AG, with the immune system representing one of the most extensively characterized. The significance of the current proposed studies is that they will provide direct mechanistic insight into the molecular mechanism by which endocannabinoids modulate T cell function, specifically IL-2 regulation. Novel preliminary results are presented demonstrating that IL-2 suppression by both AEA and 2-AG are dependent on COX-2 metabolism leading to the activation of the nuclear receptor, peroxisome proliferator activated receptor gamma (PPARgamma), independently of CB1 and CB2. Additional results are present suggesting that the specific mechanism involves the disruption of the nuclear factor of activated T cells (NFAT) by PPARgamma activation. Based on the observations described above and other preliminary data presented in the proposal, our present investigation will test the hypothesis: Suppression of IL-2 by the endocannabinoids, AEA and 2-AG, is mediated through disruption of NFAT regulation by two distinct cannabinoid receptor-independent mechanisms: (a) altered intracellular calcium regulation; and (b) activation of PPARgamma following COX-2-mediated conversion of AEA and 2-AG into PPARgamma agonists. We will test our hypothesis using the following specific aims (SA): SA1 is to characterize the role altered intracellular calcium regulation by AEA and 2-AG plays in deregulation of NFAT and, consequently, suppression of IL-2 gene expression; SA2 is to characterize the role of COX-2 on the deregulation of NFAT and suppression of IL-2 by AEA and 2-AG; SA3 is to characterize the role of PPARgamma activation by AEA and 2-AG treatment in altered NFAT regulation and suppression of IL-2; and SA4 is to identify and characterize the bioactive forms of AEA and 2-AG responsible for PPARgamma activation and to elucidate its contribution to IL- 2 suppression.

描述（由申请人提供）：这个 5 年研究计划的总体目标是阐明结构相关的内源性大麻素 anandamide (AEA) 调节 T 细胞功能和白细胞介素 2 (IL-2) 失调的分子机制。）和2-花生四烯酸甘油（2-AG）。目前，内源性大麻素系统的目的学作用尚不清楚，但越来越多的证据表明它可能对维持免疫稳态有显着贡献。大量研究已证明 AEA 和 2-AG 对生物系统产生深远影响，其中免疫系统是最广泛表征的系统之一。目前提出的研究的意义在于，它们将为内源性大麻素调节 T 细胞功能（特别是 IL-2 调节）的分子机制提供直接的见解。新的初步结果表明，AEA 和 2-AG 对 IL-2 的抑制依赖于 COX-2 代谢，导致核受体、过氧化物酶体增殖物激活受体 γ (PPARgamma) 的激活，独立于 CB1 和 CB2。其他结果表明，具体机制涉及 PPARgamma 激活对活化 T 细胞核因子 (NFAT) 的破坏。根据上述观察结果和提案中提出的其他初步数据，我们目前的研究将检验以下假设：内源性大麻素、AEA 和 2-AG 对 IL-2 的抑制是通过两种不同的大麻素受体破坏 NFAT 调节来介导的-独立机制：(a)改变细胞内钙调节； (b) COX-2介导的AEA和2-AG转化为PPARγ激动剂后PPARγ的激活。我们将使用以下具体目标 (SA) 来检验我们的假设：SA1 是为了表征 AEA 和 2-AG 改变的细胞内钙调节在 NFAT 失调中所起的作用，从而抑制 IL-2 基因表达； SA2是表征COX-2对AEA和2-AG解除NFAT调节和抑制IL-2的作用； SA3 旨在表征 AEA 和 2-AG 处理激活 PPARgamma 在改变 NFAT 调节和抑制 IL-2 中的作用； SA4 的目的是鉴定和表征负责 PPARgamma 激活的 AEA 和 2-AG 的生物活性形式，并阐明其对 IL-2 抑制的贡献。