Role of opioids signaling in immune suppression

描述（由申请人提供）：这些研究的总体目标是确定应激诱导免疫抑制的机制。压力对人类、啮齿动物和猴子的免疫系统有显著影响。先前的研究支持这样的假设，即压力源通过应激激素（如内源性阿片样物质）调节免疫调节，而不仅仅是糖皮质激素。然而，应激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，小鼠抑制应激以内源性阿片依赖的方式诱导cd95介导的脾细胞凋亡。我们的初步数据表明，磷脂酰肌醇3-激酶（PI3K）和核因子κ b （nf - κ b）信号的抑制对应激诱导的脾细胞减少具有累加效应。此外，我们还表明，抑制p53部分阻断应激诱导的脾脏淋巴细胞减少；阿片受体拮抗剂抑制应激诱导的p53表达增加。我们的总体假设是，内源性阿片类物质的产生增加对压力下的免疫抑制至关重要。此外，我们假设其机制涉及抗凋亡PI3K/NF-kappaB途径和促凋亡p53途径。第一个具体目的是研究PI3K和NF-kappaB在阿片类药物介导的免疫抑制中的作用。小鼠将分别给予或不给予PI3K/NF-kappaB抑制剂，然后给予或不给予阿片受体拮抗剂，然后进行不同时间段的身体约束应激。这些研究将着重分析淋巴细胞数量、对有丝分裂刺激的反应、细胞因子的产生和内源性阿片样物质的水平。我们打算特别关注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，作为第二个具体目标，以确定p53在阿片类药物介导的淋巴细胞减少中的作用。我们将使用p53抑制剂和p53敲除小鼠来确定p53在身体约束应激中的作用。我们将重点关注淋巴细胞数量、凋亡细胞数量、p53表达、CD95和CD95配体的表达。这些研究将引导我们理解应激环境对免疫和精神神经内分泌系统的影响。

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.