PATHOGENESIS OF FEVER IN HUMANS

人类发烧的发病机制

• 批准号: 6124162
• 负责人: Charles anthony Dinarello
• 金额: $ 43.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6124162
• 关键词: T lymphocyte; antireceptor antibody; binding proteins; biological signal transduction; clinical research; cytokine; cytokine receptors; diabetes mellitus; disease /disorder model; human subject; hyperthermia; inflammation; laboratory mouse; laboratory rabbit; melanoma; molecular cloning; monoclonal antibody; pathologic process; peritonitis; pyrogens; tissue /cell culture; transfection

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。 抗细胞因子治疗的主要靶点是肿瘤坏死因子 (TNF)和白细胞介素-1（IL-1）、多效性、促炎细胞因子。 IL-1B作为前体合成，需要称为IL-1B的蛋白酶 转化酶（ICE），用于裂解和分泌活性IL-1B。 一种新型 称为干扰素-γ-诱导因子（现称为IL-18）的细胞因子，也 需要ICE切割和分泌成活性细胞因子的是 本研究的主要目的。 ICE的特异性抑制剂减少 IL-1B和IL-18的释放以及由此产生的生物活性。 成熟IL-18在结构上与成熟IL-1B相似。 最初报告为 干扰素-γ（IFNg）在小鼠中产生的共刺激物， 内毒素血症，初步研究表明IL-18具有广泛的生物学活性， 与IL-1B类似的作用，如诱导其他 促炎细胞因子和核因子κ B的活化。 小 关于IL-18的产生和生物学特性是已知的。 的 目前的建议集中在IL-18受体信号传导的性质 复杂. 我们从人尿中纯化了可溶性IL-18结合蛋白 特异性中和IL-18的生物活性， 呈递IL-18配体结合受体的胞外结构域。 该IL-18结合的氨基酸测序导致N-末端40个氨基酸的缺失。 与600 bp的部分cDNA完全匹配的氨基酸， 存放在TIGR数据库中。 使用这600 bp作为探针，我们有 在北方杂交后观察到1.5和4.2的转录本。 我们提出 分离这两种转录本的cDNA克隆，并证明它们 是生物反应的一个不可或缺的组成部分， IL-18 针对IL-18配体的抗体将用于揭示IL-18的作用。 IL-18在疾病动物模型中的应用，特别是炎症和自身免疫性疾病 疾病 配体结合可溶性受体的抗体将用于 揭示了表面IL-18受体复合物。 定向破坏 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，我们建议解开IL-18细胞表面的性质 信号复合物，并检查这种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。