PHYSIOLOGIC ROLE OF CYTOKINES IN LPS FEVER

细胞因子在 LPS 发烧中的生理作用

• 批准号: 2671939
• 负责人: MATTHEW J KLUGER
• 金额: $ 23.39万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2671939
• 关键词: antipyretic; cytokine; gender difference; genetically modified animals; hyperthermia; hypothalamus; interleukin 1; interleukin 4; interleukin 6; laboratory mouse; laboratory rat; lipopolysaccharides; neutralizing antibody; physiology; pyrogens; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION Intraperitoneal (ip) injection of lipopolysaccharide (LPS) results in an acute phase response (APR), which includes the development of fever. As a result of recent work from several laboratories, evidence has accumulated that an ip injection of LPS induces fever by causing the release into the circulation of an endogenous pyrogen (EP), possibly interleukin-1 (IL-1), which in turn causes a rise in hypothalamic interleukin-6 (IL-6). Although there are data showing that tumor necrosis factor (TNF) is a pyrogen, most of these studies were based on injection of pharmacological doses of this cytokine. Using neutralizing antibodies or soluble receptors to TNF, Dr. Kluger has generated data showing that TNF might actually be an endogenous cryogen (EC), which limits fever. The purpose of the proposed experiments is to continue our investigations to critically evaluate the degree to which LPS-and bacterial-induced fevers actually involve these and other cytokines both in the circulation and the brain. We hypothesize that some of these cytokines are endogenous pyrogens and others are endogenous antipyretics or cryogens. The balance between the two types of mediators determines the pattern and time-course of fever. Our specific aims are to continue our studies to investigate: the pyrogenic effects of IL-1, the relationship between IL-1 and IL-6 in fever, the antipyretic or cryogenic actions of TNF, the possible role of other cytokines as endogenous antipyretics or endogenous cryogens, gender differences in febrile responses. These studies will be run in both male and female rats, and in transgenic knock- out mice deficient in the genes for various cytokines or cytokine receptors. One of the difficulties in studying the precise roles of cytokines in fever has been the inability to selectively block the biological actions of specific cytokines. With the advent of recombinant cytokines, the development of antibodies and other specific blockers, and the availability of transgenic knock-out mice, it is now possible to assess the roles of cytokines in the fever.

说明腹膜腔内注射脂多糖(LPS) 导致急性时相反应(APR)，包括发生 发烧。由于最近几个实验室的工作，有证据表明 积累了IP注射内毒素通过引起释放而引起发烧 进入内源性热原(EP)的循环，可能是白细胞介素1 (IL-1)，进而导致下丘脑IL-6(IL-6)升高。 虽然有数据表明，肿瘤坏死因子(TNF)是一种 热原，这些研究大多是基于注射药物 这种细胞因子的剂量。使用中和抗体或可溶性受体 对于肿瘤坏死因子，克鲁格博士生成的数据表明，肿瘤坏死因子实际上可能是一种 内源性冷冻剂(EC)，可抑制发烧。建议的目的是 实验是继续我们的调查，以批判性地评估 内毒素和细菌诱导的发烧实际上涉及这些和 循环和大脑中的其他细胞因子。我们假设 这些细胞因子中有些是内源性热原，另一些是内源性 退烧药或冷冻剂。两类调解人之间的平衡 决定了发烧的模式和时间进程。我们的具体目标是 继续我们的研究调查：IL-1的致热作用， IL-1和IL-6在发热、退热或低温状态下的关系 肿瘤坏死因子的作用，其他细胞因子作为内源性的可能作用 退烧药或内源性冷冻剂，发热的性别差异 回应。 这些研究将在雄性和雌性大鼠身上进行，并进行转基因 各种细胞因子或细胞因子基因缺陷的基因敲除小鼠 感受器。研究人的确切作用的困难之一是 发热中的细胞因子一直无法选择性地阻断 特定细胞因子的生物学作用。随着重组技术的出现 细胞因子，抗体和其他特定阻滞剂的发展，以及 转基因敲除小鼠的可用性，现在可以评估 细胞因子在发烧中的作用。