Pathogenesis of Fever in Humans

描述(申请人提供)：急、慢性炎症性疾病的抗细胞因子治疗已进入临床医学。抗细胞因子治疗的主要靶点是肿瘤坏死因子(TNF)和白介素1(IL-1)，它们是多效性的促炎细胞因子。IL-1受体拮抗剂(IL-1ra)已被FDA批准用于治疗类风湿性关节炎。IL-1β的其他抑制剂正在对各种疾病进行第二阶段试验。IL-18是IL-1家族的一员，与IL-1β密切相关，似乎也是疾病治疗干预的靶点。ICE的特定抑制剂减少了IL-1和IL-18的释放，从而降低了IL-18的生物活性。我们已经证明，IL-18具有与IL-1β类似的广泛作用，如诱导其他促炎细胞因子、趋化因子家族的合成、中性粒细胞的激活、Fas配体和内皮细胞黏附分子的上调。因此，宿主可能会采取各种策略来限制IL-18的生物学活性。我们分离并克隆了一种新的IL-18抑制因子--IL-18结合蛋白(IL-18BP)，它能结合和中和IL-18；IL-18BP是一种结构性表达和分泌的IL-18活性抑制因子。IL-1家族的另一个成员是IL-1同源4(IL-1H4)，它在结构上与IL-18相关，与IL-18受体α链结合，后者是IL-18受体复合体的配体结合链。然而，IL-1H4没有表现出激动剂活性。尽管重组IL-1H4可能是IL-18的“受体拮抗剂”，但它对IL-18没有受体拮抗剂活性。我们建议研究IL-1H4的功能，并评估其作为自然产生的IL-18活性抑制物在疾病中的作用。初步数据表明，IL-1H4与IL-18BP结合，该复合体招募IL-18受体复合体的信号β链，从而剥夺细胞进行信号转导的β链。因此，IL-1H4似乎起到了“诱饵”细胞因子的作用。建议的研究旨在利用炎症性疾病的动物模型来证明IL-1H4通过这种新的机制在疾病中发挥作用。人IL-1H4似乎降低了小鼠IL-18的活性，因此，我们将产生过表达人IL-1H4的转基因小鼠，并用IL-18依赖的疾病模型来攻击这些小鼠。这些研究可能对使用IL-1H4治疗IL-18相关疾病有意义。

DESCRIPTION (provided by applicant): 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. The IL-1 receptor antagonist (IL-1Ra) has been approved by the FDA for the treatment of rheumatoid arthritis. Other inhibitors of the IL-1 beta are in Phase II trials for various diseases. IL-18, a member of the IL-1 family and closely related to IL-1 beta, also appears to be a target for therapeutic intervention in disease. Specific inhibitors of ICE reduce the release and hence the biological activity of both IL-1 and IL-18. We have demonstrated that IL-18 has broad effects similar to those of IL-1 beta such as inducing the synthesis of other pro-inflammatory cytokines, the family of chemokines, activation of neutrophils, and upregulation of Fas ligand and endothelial adhesion molecules. Therefore, the host likely mounts various strategies to limit the biological activities of IL-18. We isolated and cloned a novel IL-18 inhibitor, the IL-18 binding protein (IL-18BP), which binds and neutralizes IL-18; the IL-18BP is a constitutively expressed and secreted inhibitor of IL-18 activity. Another member of the IL-1 family is the IL-1 homologue 4 (IL-1H4), which is structurally related to IL-18, binds to IL-18 receptor alpha chain, which is the ligand binding chain of the IL-18 receptor complex. However, IL-1H4 exhibits no agonist activities. Although likely to be the "receptor antagonist" for IL-18, recombinant IL-1H4 exhibits no receptor antagonist activities for IL-18. We propose to study the function of IL-1 H4 and assess its role in disease as a naturally occurring inhibitor of IL-18 activity. Preliminary data indicate that IL-1H4 binds to the IL-18BP and that this complex recruits the signaling beta chain of the IL-18 receptor complex, thereby depriving the cell of the beta chain for signal transduction. As such, IL-1H4 appears to function as a "decoy" cytokine. The proposed studies are intended to show that IL-1H4 plays a role in disease via this novel mechanism using animal models of inflammatory disease. Human IL-1H4 appears to reduce the activities of mouse IL-18, therefore, we will generate transgenic mice overexpressing human IL-1H4 and challenge these mice using IL-18-dependent models of disease. These studies may have implications for the use of IL-1H4 to treat IL-18-related diseases.