PATHOGENESIS OF FEVER IN HUMANS

人类发烧的发病机制

基本信息

批准号：
6033541
负责人：
Charles anthony Dinarello
金额：
$ 42.49万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-12-01 至 2002-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from Investigator's abstract): Anti-cytokine therapy for acute and chronic inflammatory diseases has entered clinical medicine. The main targets for anti-cytokine-based therapies are tumor necrosis factor (TNF) and interleukin-1 (IL-1), pleiotropic, proinflammatory cytokines. IL-1B is synthesized as a precursor requiring a protease called IL-1B converting enzyme (ICE) for cleavage and secretion of active IL-1B. A novel cytokine called interferon-gamma-inducing factor (now named IL-18), also requiring ICE for cleavage and secretion to an active cytokine, is the primary objective for the present study. Specific inhibitors of ICE reduce the release and hence the biological activity of both IL-1B and IL-18. Mature IL-18 is structurally similar to mature IL-1B. Initially reported as a co-stimulant of interferon-gamma (IFNg) production in mice during endotoxemia, preliminary studies demonstrate that IL-18 has broad biological effects similar to those of IL-1B such as inducing the synthesis of other pro-inflammatory cytokines and activation of nuclear factor kappa-B. Little is known about the production and biological properties of IL-18. The current proposal focuses on the nature of the IL-18 receptor signaling complex. We have purified from human urine a soluble IL-18 binding protein which specifically neutralizes the biological activity of IL-18 and likely presents the extracellular domain of the IL-18 ligand binding receptor. Amino acid sequencing of this IL-18 binding resulted in N-terminal 40 amino acids which are a perfect match to a partial cDNA of 600 bp recently deposited in the TIGR data base. Using these 600 bp as a probe, we have observed a 1.5 and 4.2 transcript upon Northern hybridization. We propose to isolate cDNA clones for these two transcripts and demonstrate that they are an integral and essential component of the biological response signaled by IL-18. Antibodies to the IL-18 ligand will be used to reveal the role of IL-18 in animal models of disease, particularly inflammatory and autoimmune diseases. Antibodies to the ligand binding soluble receptor will be used to reveal the surface IL-18 receptor complexes. Targeted disruption of the IL-18 ligand-binding receptor will be carried out in mice with the goal of assessing the biological role IL-18 in health and disease. In these studies, we propose to unravel the nature of the IL-18 cell surface signaling complex and to examine whether this cytokine contributes to inflammatory disease. These studies will broaden the present concepts of proinflammatory cytokines in pathological processes.

描述（改编自研究者的摘要）：抗细胞因子治疗用于急、慢性炎症性疾病已进入临床医学。抗细胞因子疗法的主要靶点是肿瘤坏死因子 (TNF) 和白介素-1 (IL-1)，多效性促炎细胞因子。 IL-1B 作为前体合成，需要一种称为 IL-1B 的蛋白酶用于裂解和分泌活性 IL-1B 的转换酶 (ICE)。一本小说称为干扰素γ诱导因子（现称为 IL-18）的细胞因子，也称为需要 ICE 来裂解和分泌活性细胞因子，本研究的主要目标。 ICE 的特异性抑制剂可减少 IL-1B 和 IL-18 的释放及其生物活性。成熟的 IL-18 在结构上与成熟的 IL-1B 相似。最初报道为小鼠体内干扰素-γ (IFNg) 产生的共刺激剂内毒素血症，初步研究表明IL-18具有广泛的生物学作用与 IL-1B 类似的作用，例如诱导其他物质的合成促炎细胞因子和核因子 kappa-B 的激活。小的已知 IL-18 的产生和生物学特性。这目前的提案重点关注 IL-18 受体信号传导的性质复杂的。我们从人尿中纯化出可溶性 IL-18 结合蛋白它专门中和 IL-18 的生物活性，并且可能呈现 IL-18 配体结合受体的胞外结构域。 IL-18 结合的氨基酸测序产生 N 端 40 个氨基酸最近与600 bp的部分cDNA完美匹配的酸存入 TIGR 数据库。使用这 600 bp 作为探针，我们有在 Northern 杂交中观察到 1.5 和 4.2 转录本。我们建议分离这两个转录本的 cDNA 克隆并证明它们是所发出的生物反应的一个不可或缺的组成部分通过IL-18。 IL-18 配体的抗体将用于揭示疾病动物模型中的 IL-18，特别是炎症和自身免疫性疾病模型疾病。配体结合可溶性受体的抗体将用于揭示表面 IL-18 受体复合物。有针对性地破坏 IL-18配体结合受体将在小鼠中进行，目的是评估 IL-18 在健康和疾病中的生物学作用。在这些研究中，我们建议解开 IL-18 细胞表面的性质信号复合物并检查该细胞因子是否有助于炎症性疾病。这些研究将拓宽目前的概念病理过程中的促炎细胞因子。