PHYSIOLOGIC ROLE OF CYTOKINES IN LPS FEVER

腹腔注射脂多糖（LPS） 导致急性期反应（APR），其中包括 发烧 由于最近几个实验室的工作，证据表明， 累积的是，ip注射LPS通过引起释放 进入内源性热原（EP）的循环，可能是白细胞介素-1 （IL-1），这反过来又引起下丘脑白细胞介素-6（IL-6）的升高。 虽然有数据显示肿瘤坏死因子（TNF）是一种 热原，这些研究中的大多数是基于注射药理学 这种细胞因子的剂量。 使用中和抗体或可溶性受体 Kluger博士生成的数据显示，TNF实际上可能是一种 内源性冷冻剂（EC），可限制发热。 建议的目的 实验是继续我们的调查，以批判性地评估 LPS和细菌引起的发热实际上涉及这些的程度， 循环和大脑中的其他细胞因子。 我们假设 这些细胞因子中的一些是内源性热原，而另一些是内源性的 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的致热效应， IL-1和IL-6在发热、解热、降温中的关系 TNF的作用，其他内源性细胞因子的可能作用， 解热药或内源性冷冻剂，发热的性别差异 应答 这些研究将在雄性和雌性大鼠以及转基因大鼠中进行。 各种细胞因子或细胞因子基因缺陷的敲除小鼠 受体。 在研究的确切作用的困难之一， 发烧中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 细胞因子在发热中的作用

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.