Role of opioids signaling in immune suppression

阿片类信号传导在免疫抑制中的作用

• 批准号: 6953489
• 负责人: DELING YIN
• 金额: $ 10.95万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953489
• 关键词: CD95 molecule; apoptosis; cell sorting; endogenous opioid; gene expression; genetically modified animals; immunosuppression; inhibitor /antagonist; laboratory mouse; lymphocyte; neuroendocrine system; nuclear factor kappa beta; p53 gene /protein; phosphatidylinositol 3 kinase; psychological stressor; psychoneuroimmunology; stress

DESCRIPTION (provided by applicant): The overall goal of these studies is to determine the mechanism(s) underlying stress-induced immune suppression. Stress has significant effects on the immune system of humans, rodents, and monkeys. Previous studies support the hypothesis that stressors modulate immune regulation through stress hormones such as endogenous opioids, other than exclusively glucocorticoids. However, the mechanisms by which stress affect the immune and neuroendocrine systems remain to be established. Our recent studies revealed that restraint stress of mice induces CD95-mediated apoptosis in splenocytes in an endogenous opioid-dependent manner. Our preliminary data showed that inhibition of phosphatidylinositol 3-kinase (PI3K) and nuclear factor kappaB (NF-kappaB) signaling exerts an additive effect on stress-induced splenocyte reduction. In addition, we have also shown that inhibition of p53 partially blocks stress-induced lymphocyte reduction in the spleen; and that opioid receptor antagonists inhibit the stress-induced increase in p53 expression. Our overall hypothesis is that increased production of endogenous opioids is critical to immune suppression during stress. Moreover, we postulate that the mechanism involves the anti-apoptotic PI3K/NF-kappaB pathway and the pro-apoptotic p53 pathway. The first specific aim is to study the contributions of PI3K and NF-kappaB in opioids-mediated immune suppression. Mice will be treated with or without PI3K/NF-kappaB inhibitors followed by treatment with or without opioid receptor antagonists, and then subjected to physical restraint stress for different time periods. These studies will emphasize an analysis of lymphocyte number, response to mitogenic stimulation, cytokine production, and the level of endogenous opioids. We intend to give particular attention to examine the effects of endogenous opioids and PI3K/NF-kappaB on immune responses in vivo. We also propose studies, as the second specific aim, to determine the role of p53 in opioids-mediated lymphocyte reduction. We will use a p53 inhibitor and p53 knockout mice to determine the role of p53 in physical restraint stress. Our emphasis will be on lymphocyte number, the number of apoptotic cells, p53 expression, and the expression of CD95 and CD95 ligand. These studies should lead to our understanding of the effects of a stress environment on the immune and psychoneuroendocrine systems.

描述（由申请人提供）：这些研究的总体目标是确定应激诱导的免疫抑制的机制。压力对人类，啮齿动物和猴子的免疫系统具有显着影响。先前的研究支持以下假设：压力源通过诸如内源性阿片类药物等应激激素（仅限于糖皮质激素）来调节免疫调节。但是，压力影响免疫和神经内分泌系统的机制仍有待确定。我们最近的研究表明，小鼠的约束应激以内源性阿片类药物依赖性方式诱导脾细胞中CD95介导的凋亡。我们的初步数据表明，抑制磷脂酰肌醇3-激酶（PI3K）和核因子Kappab（NF-kappab）信号传导对压力诱导的脾细胞减少产生了添加作用。此外，我们还表明，抑制p53部分阻断了脾脏淋巴细胞的减少。阿片受体拮抗剂抑制了应力诱导的p53表达增加。我们的总体假设是，内源性阿片类药物的产生对于压力期间的免疫抑制至关重要。此外，我们假设该机制涉及抗凋亡PI3K/NF-KAPPAB途径和促凋亡P53途径。第一个具体目的是研究阿片类药物介导的免疫抑制中PI3K和NF-kappab的贡献。小鼠将接受或没有PI3K/NF-kappab抑制剂进行治疗，然后进行治疗或没有阿片类药物受体拮抗剂的治疗，然后在不同的时间段内遭受身体约束应力。这些研究将强调淋巴细胞数，对有丝分裂刺激的反应，细胞因子产生和内源性阿片类药物水平的分析。我们打算特别注意检查内源性阿片类药物和PI3K/NF-kappab对体内免疫反应的影响。我们还提出研究，作为第二个特定目的，以确定p53在阿片类药物介导的淋巴细胞还原中的作用。我们将使用p53抑制剂和p53敲除小鼠来确定p53在物理约束应力中的作用。我们的重点是淋巴细胞数，凋亡细胞的数量，p53表达以及CD95和CD95配体的表达。这些研究应导致我们对压力环境对免疫和心理内分泌系统的影响的理解。