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

在以前的实验中，我们可以证明I型和II型干扰素，而不是III型干扰素，能够诱导转录因子IRF1的蛋白质翻译。在肝细胞和肝窦内皮细胞中，干扰素介导的IRF1合成诱导关键细胞因子IL-7的产生，该因子介导巨噬细胞中GSK3的磷酸化(即失活)。这导致巨噬细胞对内毒素的耐受性减弱，导致促炎细胞因子的产生增加。此外，IL-7对于一个完整的T细胞隔间是必需的。值得注意的是，我们观察到，与健康对照组相比，肝硬变患者的血清IL-7水平降低，可能是由于肝脏合成受损，这与进展期肝硬变患者其他细胞因子的过度产生形成了对比。因此，我们推测，通过改善抗菌巨噬细胞功能和T细胞免疫，治疗性应用IL-7可能有益于预防和改善感染引发的急性慢性肝衰竭，而IL-7的促炎特性在无菌(酒精)急性慢性肝衰竭中可能是不利的。这一假说将在细胞培养模型、患者样本和酒精性肝炎并发全身炎症反应综合征和脓毒症的动物模型中进行评估。

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.