Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity

Front Immunol. 2021 Jan 14:11:581352. doi: 10.3389/fimmu.2020.581352. eCollection 2020.


Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.

Keywords: acute-on-chronic liver failure; cytokines; inflammation; interferons; liver cirrhosis; liver immunology; macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-On-Chronic Liver Failure / immunology
  • Cell Line
  • Coculture Techniques
  • Cohort Studies
  • Glycogen Synthase Kinase 3 / metabolism
  • Hep G2 Cells
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-1 / biosynthesis*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / immunology
  • Interferon Type I / immunology*
  • Interferon-gamma / immunology*
  • Interleukin-7 / biosynthesis*
  • Liver / immunology*
  • Liver / metabolism
  • Liver Cirrhosis / immunology
  • Macrophages / immunology
  • Prospective Studies
  • Protein Biosynthesis
  • Signal Transduction / immunology


  • IL7 protein, human
  • Interferon Regulatory Factor-1
  • Interferon Type I
  • Interleukin-7
  • Interferon-gamma
  • Glycogen Synthase Kinase 3