PHYSIOLOGIC ROLE OF CYTOKINES IN LPS FEVER

描述 腹腔内 (ip) 注射脂多糖 (LPS) 导致急性期反应（APR），其中包括发展 发烧。 多个实验室最近的工作结果表明， 累积表明，腹腔注射 LPS 通过引起释放而引起发热 进入内源性热原 (EP) 的循环，可能是白介素-1 (IL-1)，进而导致下丘脑白细胞介素 6 (IL-6) 升高。 虽然有数据表明肿瘤坏死因子（TNF）是一种 热原，大多数这些研究都是基于注射药理学 该细胞因子的剂量。 使用中和抗体或可溶性受体 对于 TNF，Kluger 博士生成的数据表明 TNF 实际上可能是一种 内源性冷冻剂 (EC)，可限制发热。 拟议的目的 实验是为了继续我们的调查以批判性地评估 LPS 和细菌引起的发烧实际上涉及这些和 循环系统和大脑中的其他细胞因子。 我们假设 其中一些细胞因子是内源性致热原，另一些是内源性的 退热药或冷冻剂。 两类中介者之间的平衡 决定发烧的模式和时间进程。 我们的具体目标是 继续我们的研究来调查：IL-1 的热原作用， IL-1和IL-6在发热、解热或低温中的关系 TNF 的作用，其他细胞因子作为内源性的可能作用 退热药或内源性冷冻剂，发热的性别差异 回应。 这些研究将在雄性和雌性大鼠以及转基因大鼠中进行 缺乏多种细胞因子或细胞因子基因的敲除小鼠 受体。 研究其精确作用的困难之一 发烧时的细胞因子无法选择性地阻断 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、抗体和其他特异性阻断剂的产生，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。

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.