Role of interleukin-7 in alcoholic and infection-triggered acute-on-chronic liver failure

IL-7 在酒精和感染引发的慢性肝衰竭中的作用

• 批准号: 436377529
• 负责人: Professor Dr. Christian Lange
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik II - Großhadern
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/436377529?language=en
• 关键词: Role; interleukin; alcoholic; infection; triggered

In previous experiments we could show that type I- and II-interferons, but not type III-interferon, are capable to induce protein translation of the transcription factor IRF1. In hepatocytes and liver sinusoidel endothelial cells, interferon-mediated IRF1 synthesis induces production of the key cytokine IL-7, which mediates phosphorylation (i.e. inactivation) of the kinase GSK3 in macrophages. This results in an attenuation of LPS tolerance in macrophages with the consequence of an increased production of proinflammatory cytokines. In addition, IL-7 is required for an intact T cell compartment. Of note, we have observed reduced serum levels of IL-7 in patients with liver cirrhosis compared to healthy controls, probably due to impaired hepatic synthesis, which is contrasted by the excessive production of other cytokines in advanced liver cirrhosis. We therefore hypothesize that therapeutically administered IL-7 may be beneficial in preventing and ameliorating infection-triggered acute-on-chronic liver failure by improving antibacterial macrophage function and T cell immunity, whereas the pro-inflammatory features of IL-7 may be adverse in sterile (alcoholic) acute-on-chronic liver failure. This hypothesis will be assessed in cell culture models, patient samples and animal models of alcoholic hepatitis complicated by SIRS and sepsis.

在以前的实验中，我们可以表明，I型和II型干扰素，但不是III型干扰素，能够诱导转录因子IRF 1的蛋白质翻译。在肝细胞和肝窦状内皮细胞中，干扰素介导的IRF 1合成诱导关键细胞因子IL-7的产生，IL-7介导巨噬细胞中激酶GSK 3的磷酸化（即失活）。这导致巨噬细胞中LPS耐受性的减弱，其结果是促炎细胞因子的产生增加。此外，IL-7是完整的T细胞区室所必需的。值得注意的是，我们已经观察到与健康对照相比，肝硬化患者中IL-7的血清水平降低，这可能是由于肝合成受损，这与晚期肝硬化中其他细胞因子的过度产生形成对比。因此，我们假设治疗性施用IL-7可能通过改善抗菌巨噬细胞功能和T细胞免疫而有益于预防和改善感染触发的慢加急性肝衰竭，而IL-7的促炎特征可能对无菌（酒精性）慢加急性肝衰竭不利。将在酒精性肝炎并发SIRS和脓毒症的细胞培养模型、患者样本和动物模型中评估该假设。