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

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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.