ALCOHOL AND BRAIN INTERLEUKIN 1

酒精和脑白细胞介素 1

• 批准号: 2748467
• 负责人: Michael Selmanoff
• 金额: $ 10.43万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2748467
• 关键词: RNase protection assay; alcoholism /alcohol abuse; artificial immunosuppression; astrocytes; embryo /fetus tissue /cell culture; embryo /fetus toxicology; ethanol; gene induction /repression; hypothalamic pituitary axis; hypothalamus; immunocytochemistry; interleukin 1; laboratory rat; microglia; neuroimmunomodulation; neurons; nutrition related tag

APPLICANT S ABSTRACT: Alcohol (ethanol-ETOH) abuse produces pathological effects including various brain dysfunction and immune impairment associated with increased susceptibility to various infections. One central abnormality is EtOH activation of the hypothalamic-pituitary-adrenal (HPA) axis. Although stimulation of hypothalamic corticotropin-releasing hormone (CRH) producing neurons is critical for EtOH-induced HPA activation, a precise understanding of how this occurs remains to be established. Of potential relevance, interleukin (IL)-l potently stimulates the HPA axis, is produced in hypothalamus, and stimulates common cellular signals as EtOH. Preliminary results in our laboratory show that EtOH increases IL-1beta mRNA in primary hypothalamic neuronal and glial cultures. Thus, EtOH could activate the HPA axis by increasing hypothalamic IL-1 signaling. The proposed hypothesis is that EtOH induces hypothalamic IL-1, in vitro and in vivo studies will demonstrate: 1) effects of acute and chronic EtOH on expression of IL-1beta mRNA(RNase protection assay) and IL-1beta (immunocytochemistry-ICC) and on immune/cytokine stimulation in fetal rat hypothalamic neuronal, astrocytic and microglial cultures, and 2) effects of an EtOH diet on adult rat hypothalamic IL-1beta mRNA and IL-1beta and HPA axis activation. HPA axis activation occurs in alcoholics and can cause peripheral immunosuppression via glucocorticoid-dependent and -independent mechanisms. Recognizing that central effects of IL-1 can also cause peripheral immunosuppression via both these pathways, EtOH induction of brain IL-1 could lead to immunosuppression via these central mechanisms. The well recognized impaired immunity in alcoholics could be further attenuated by mechanisms involving central cytokine dysfunction which could contribute to the high prevalence of HIV infection in alcoholics and progression to AIDS. Long term goals are to learn about mechanisms mediating EtOH effects on the brain IL-1 system and to determine the role and significance of these alterations relative to EtOH-induced HPA axis activation and peripheral immunosuppression.

申请者S摘要：酒精(乙醇-乙醇)滥用会导致病态 影响包括各种脑功能障碍和相关的免疫损伤 对各种感染的易感性增加。一个中环 异常是下丘脑-垂体-肾上腺(HPA)的乙醇激活 轴心。虽然刺激下丘脑促肾上腺皮质激素释放激素 促肾上腺皮质激素释放激素(CRH)产生的神经元对乙醇诱导的HPA激活至关重要，a 对于这种情况是如何发生的，还有待于建立准确的理解。的 潜在的相关性，白细胞介素(IL)-L有力地刺激HPA轴，是 在下丘脑产生，并刺激常见的细胞信号，如乙醇。 我们实验室的初步结果表明，乙醇增加了IL-1β的mRNA 在原代培养的下丘脑神经元和神经胶质细胞中。因此，Etoh可以 通过增加下丘脑IL-1信号激活HPA轴。这个 提出的假说是乙醇在体外和体外诱导下丘脑IL-1。 活体研究将证明：1)急性和慢性乙醇对 核糖核酸酶保护法检测IL-1β和IL-1β的表达 (免疫细胞化学-ICC)及对胎鼠免疫/细胞因子刺激的影响 下丘脑神经元、星形胶质细胞和小胶质细胞培养，以及2) 乙醇饲料对成年大鼠下丘脑IL-1β、IL-1β和HPA的影响 轴心激活。 HPA轴激活发生在酗酒者身上，并可导致外周 通过糖皮质激素依赖和非依赖机制的免疫抑制。 认识到IL-1的中枢作用也可以导致外周 通过这两个途径的免疫抑制，乙醇诱导脑内IL-1 可能通过这些中枢机制导致免疫抑制。这口井 酗酒者公认的免疫力受损可通过以下方法进一步减弱 涉及中枢细胞因子功能障碍的机制可能有助于 酗酒者中艾滋病毒感染的高流行率和向艾滋病的进展。 长期目标是了解乙醇在体内的作用机制。 脑内IL-1系统及其确定的作用和意义 乙醇诱导的HPA轴激活和外周的改变 免疫抑制。