ALCOHOL/INTERLEUKIN INTERACTIONS ON THE HPA AXIS

HPA 轴上的酒精/白介素相互作用

• 批准号: 2044932
• 负责人: CATHERINE L RIVIER
• 金额: $ 38.73万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2044932
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; corticotropin releasing factor; embryo /fetus toxicology; gender difference; glucocorticoids; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary axis; immunity; interleukin 1; laboratory rat; lipopolysaccharides; messenger RNA; nitric oxide; northern blottings; pituitary adrenal axis; postnatal growth disorder; prenatal stress; radioimmunoassay; secretory immune system; vasopressins

As part of the functional relationship which exists between the immune and the neuroendocrine systems, proteins released by activated immune cells, called interleukins (ILs) or cytokines, convey the occurrence of immune stimulation to the hypothalamic-pituitary-adrenal (HPA) axis. The resulting increased activity of the HPA axis induced by ILs is essential to allow the organism to mount proper immune, endocrine and metabolic responses to an antigenic challenge. Consequently, pathological secretory rates of corticotropin-releasing factor (CRF), ACTH and/or corticosteroids during antigenic challenges can result in increased susceptibility immunologic disorders. Alcoholics and children of alcoholic mothers suffer from an increased occurrence of both infectious and inflammatory diseases, conditions that are associated, respectively, with abnormally elevated or blunted activity of the HPA axis. The distribution of these diseases in predisposed individuals indicates a distribution that is skewed by gender. Based on our animal studies, we hypothesize that alcohol-induced changes in the normal response of the HPA axis to immune signals participate in these pathologies, and that the sex steroid milieu influences both the stimulatory effect of cytokines on neuroendocrine functions, and the ability of alcohol to alter these responses. Our studies are therefore aimed at gaining a better understanding of the mechanisms responsible for the ability of alcohol alters the normal functional link between the immune system and the HPA axis. We have shown that exposure to alcohol during embryonic development or postnatally alters the stimulatory effect of ILs on ACTH and corticosterone release. Studies described in the present proposal will extend these results and explore the mechanisms responsible for the influence of alcohol. We will use IL-1beta, endotoxins or a small volume of turpentine to investigate the effect of a single cytokine, of a cascade of cytokines, or of a true inflammatory response, to probe the mechanisms through which alcohol disrupts the response of the HPA axis to immune signals. Under Specific Aim 1, we will study the influence of gender and sex steroids, the role of CRF, vasopressin and their receptors, and of nitric oxide, in mediating the influence of prenatal alcohol exposure on the response of the HPA axis to immune challenges. Under Specific Aim 2, a similar approach will be used to investigate the ability of post-natal alcohol administration to alter the response of the HPA axis of peripubertal and mature rats to cytokines. In both sets of experiments, sophisticated surgical approaches will be combined with techniques of molecular biology to provide a comprehensive investigation of the hypotheses we propose to test. We believe that the concept we present is original, and that the information gained from our studies will form the basis for a novel approach to the treatment of alcohol-related immune dysfunction.

作为免疫与免疫之间的功能关系的一部分 神经内分泌系统，激活的免疫细胞释放的蛋白质， 称为白细胞介素（ILS）或细胞因子，传达免疫的发生 刺激下丘脑 - 垂体 - 肾上腺（HPA）轴。 这 ILS诱导的HPA轴活动的增加是必不可少的 允许生物体安装适当的免疫，内分泌和代谢 对抗原挑战的反应。 因此，病理分泌 皮质激素释放因子（CRF），ACTH和/或 抗原挑战期间皮质类固醇可能导致增加 敏感性免疫疾病。 酗酒者和酗酒母亲的子女遭受增加 传染病和炎症性疾病的发生，这是 分别与异常升高或钝性活动相关 HPA轴的。 这些疾病在易感性中的分布 个体表示性别偏斜的分布。 基于 我们的动物研究，我们假设酒精引起的变化 HPA轴对免疫信号的正常响应参与这些 病理学，性类固醇环境影响 细胞因子对神经内分泌功能的刺激作用，并 酒精改变这些反应的能力。 因此，我们的研究是 旨在更好地了解负责的机制 酒精的能力改变了正常的功能联系 免疫系统和HPA轴。 我们已经表明，在胚胎发育期间暴露于酒精或 产后改变IL对ACTH和ACTH的刺激作用 皮质酮释放。 本提案中描述的研究将 扩展这些结果并探索负责 酒精的影响。 我们将使用IL-1Beta，内毒素或少量 松节油研究单细胞因子的作用，级联反应的作用 细胞因子或真正的炎症反应的探测机制 酒精破坏了HPA轴对免疫的反应 信号。 在特定目标1下，我们将研究性别和 性类固醇，CRF，加压素及其受体的作用以及 一氧化氮，介导产前酒精暴露对 HPA轴对免疫挑战的反应。 在特定目标2下， 类似的方法将用于研究产后的能力 饮酒以改变HPA轴的响应 腹膜和成熟大鼠到细胞因子。 在两组实验中， 精致的手术方法将与 分子生物学，以全面研究 我们建议测试的假设。 我们相信我们提出的概念是 原始的，从我们的研究中获得的信息将形成 一种新型方法治疗酒精相关免疫的基础 功能障碍。