PATHOGENENESIS OF FEVER IN HUMANS

该建议涉及白细胞介素-1（IL-1）作为一种关键的介导剂， 宿主对微生物入侵的反应，炎症，免疫 反应和伤害。 IL-1是第一个也是最重要的一个 在感染或损伤开始后合成的分子。 IL-1的许多作用与病理过程有关， 宿主有合成，加工， IL-1的转运和活性受到调节。 这项建议 研究这些机制。 实验设计 探索人血单核细胞产生IL-1的能力。 高达 5%的总多聚腺苷酸化RNA编码IL-1-β， 刺激后的单核细胞。 控制翻译的机制 将这种RNA转化为IL-1蛋白，而其他机制似乎 控制初级翻译产品到 生物活性IL-1。 转录、翻译和处理 IL-1在血单核细胞中的表达与培养细胞中的表达不同 线 因此，这些实验集中在每一个 健康人循环血细胞产生IL-1的步骤， 在疾病和各种疾病的影响下， 物质. 将采用特殊的方法来防止 单核细胞中IL-1的转录由于粘附于表面。 两种新开发的IL-1-β和IL-1-β放射免疫测定法 阿尔法将被用于一项大型研究，以确定构成 “正常”的IL-1生产。 免疫沉淀和 使用特异性非交叉反应抗体的免疫荧光 将用于检测IL-1的大小和细胞定位。 IL-1的特异性生物学活性随分子水平的不同而不同， 的结构与功能关系的研究 提出IL-1是为了鉴定推定的活性位点。 将对合成肽进行评价， 与单核细胞IL-1的天然片段相关。 中毒性休克血流动力学休克动物模型的建立 综合征毒素是用来评估全身效应的 IL-1、其片段和抑制其生物活性的物质 活动 将使用两种临床模型来研究IL-1 人类受试者的生产：补充鱼油的影响 饮食和血液透析。 这些研究补充了 IL-1产生的分子调控研究。 最后，这些研究检查了IL-1的产生和活性， 在内源性放大和抑制的模型中。

This proposal concerns interleukin-1 (IL-1) as a key mediator of host responses to microbial invasion, inflammation, immunological reaction and injury. IL-1 is one of the first and most prominent molecular synthesized following the onset of infection or injury. Many of IL-1's effects are involved with pathological processes, and the host has mechanisms by which synthesis, processing, transport and activities of IL-1 are regulated. This proposal studies these various mechanisms. The experiments are designed to explore IL-1 production from human blood monocytes. Up to 5% of the total polyadenylated RNA codes for IL-1-beta in monocytes after stimulation. Mechanisms control the translation of this RNA into IL-1 protein whereas other mechanisms seem to control processing of the primary translation product into biologically active IL-1. Transcription, translation and processing of IL-1 are different in blood monocytes than in cultured cells lines. Therefore, these experiments are focused on each of the steps of IL-1 production in circulating human blood cells in health, in disease and under the influence of various disease modifying substances. special methods will be employed that prevent the transcription of Il-1 in monocytes due to adherence to surfaces. Two newly developed radioimmunoassays for IL-1-beta and Il-1- alpha will be used in a large study to establish what constitutes "normal" Il-1 production. Immunoprecipitation and immunofluorescence using specific, non-cross reacting antibodies will be used to detect the sizes and cellular localization of IL-1. The specific biological activities of Il-1 differ with the molecular size and hence studies on the structure-function relationship of IL-1 are proposed in order to identify a putative active site(s). The evaluation of synthetic peptides will be performed and correlated with naturally occurring fragments of monocyte Il-1. An animal model of hemodynamic shock using toxic shock syndrome toxin is to be used to evaluate the systemic effects of Il-1, its fragments and substances that inhibit its biological activities. Two clinical models will be used to study Il-1 production in human subjects: the effect of supplemental fish oil diet and hemodialysis. These studies complement the basic investigations on the molecular control of IL-1 production. Finally, these studies examine the production and activity of IL-1 in models of endogenous amplification and inhibition.