PATHOGENESIS OF FEVER IN HUMANS

描述(摘自研究人员摘要)：抗细胞因子治疗 对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。 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是作为需要一种名为IL-1B的蛋白酶的前体合成的 分解和分泌活性IL-1B的转换酶(ICE)。一本小说 称为干扰素-伽马诱导因子(现在称为IL-18)的细胞因子，也 需要ICE来切割和分泌活性细胞因子，是 本研究的主要目标。ICE还原的特异性抑制剂 IL-1B和IL-18的释放和生物活性。 成熟的IL-18在结构上与成熟的IL-1B相似。最初报告为 在小鼠体内产生干扰素-γ(IFNG)的辅助刺激剂 内毒素血症，初步研究表明IL-18具有广泛的生物学意义 与IL-1B类似的作用，如诱导其他 促炎细胞因子与核因子-kappaB的激活一点儿 已知IL-18的产生和生物学特性。这个 目前的建议集中在IL-18受体信号转导的性质上 很复杂。我们从人尿中提纯了一种可溶的IL-18结合蛋白 它专门中和了IL-18的生物活性，很可能 介绍了IL-18配体结合受体的胞外区。 对这种IL-18结合的氨基酸进行测序，结果是N端有40个氨基酸 与最近一段600bp的部分c DNA完全匹配的酸 存放在TIGR数据库中。使用这600个碱基对作为探针，我们有 Northern杂交观察到1.5和4.2的转录本。我们建议 分离这两个转录本的cDNA克隆，并证明它们 是发出信号的生物反应的一个不可或缺的重要组成部分 被IL-18感染。IL-18配体的抗体将被用来揭示 IL-18在疾病动物模型中的作用，特别是炎症和自身免疫 疾病。与配体结合的可溶性受体的抗体将用于 揭示表面IL-18受体复合体。有针对性地扰乱 IL-18配体结合受体将在小鼠身上进行，目标是 评估IL-18在健康和疾病中的生物学作用。在这些 研究中，我们建议揭开IL-18细胞表面的本质 并检测该细胞因子是否参与了 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。

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.