Pathogenesis of Fever in Humans

急慢性炎症性疾病的抗细胞因子治疗已进入临床医学。主 抗细胞因子治疗的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-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，似乎也是治疗的靶点 对疾病的干预。ICE的特定抑制剂减少了这两种物质的释放，从而降低了它们的生物活性 IL-1和IL-18。我们已经证明，IL-18具有与IL-1β类似的广泛作用，例如 诱导其他促炎细胞因子的合成，趋化因子家族，激活 中性粒细胞，上调Fas配体和内皮细胞黏附分子。因此，东道主很可能 采取各种策略限制IL-18的生物活性。我们分离并克隆了一种新的IL-18 抑制物，IL-18结合蛋白(IL-18BP)，与IL-18结合并中和；IL-18BP是一种 组成性表达和分泌IL-18活性抑制物。IL-1家族的另一个成员是IL-1 同系物4(IL-1H4)在结构上与IL-18相关，与IL-18受体α链结合，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。虽然 重组IL-1H4可能是IL-18的受体拮抗剂，但没有受体拮抗剂活性 为了IL-18。我们建议研究IL-1 H4的功能，并评估其在自然发生的疾病中的作用 IL-18活性的抑制物。初步数据表明，IL-1H4与IL-18BP结合，该复合体 重新招募IL-18受体复合体的信号β链，从而剥夺细胞的β链 用于信号转导。因此，IL-1H4似乎起到了“诱饵”细胞因子的作用。建议进行的研究 旨在通过使用动物模型显示IL-1 H4通过这种新机制在疾病中发挥作用 炎症性疾病。人IL-1H4似乎降低了小鼠IL-18的活性，因此，我们将 建立高表达人IL-1H4的转基因小鼠并用依赖IL-18的方法攻击这些小鼠 疾病的模型。这些研究可能对使用IL-1 H4治疗IL-18相关疾病有意义 疾病。

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-1 H4 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-1 H4 to treat IL-18-related diseases.