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Translation of IRF-1 restricts hepatic interleukin-7 production to types I and II interferons: implications for hepatic immunity
- 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.
Verfasserangaben: | Sabrina Rüschenbaum, Chengcong Cai, Matthias Schmidt, Katharina Schwarzkopf, Ulf Dittmer, Stefan ZeuzemORCiDGND, Christoph WelschORCiDGND, Christian Michael Lange |
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URN: | urn:nbn:de:hebis:30:3-574356 |
DOI: | https://doi.org/10.3389/fimmu.2020.581352 |
ISSN: | 1664-3224 |
Titel des übergeordneten Werkes (Englisch): | Frontiers in immunology |
Verlag: | Frontiers Media |
Verlagsort: | Lausanne |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Veröffentlichung (online): | 14.01.2021 |
Datum der Erstveröffentlichung: | 14.01.2021 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 28.01.2021 |
Freies Schlagwort / Tag: | acute-on-chronic liver failure; cytokines; inflammation; interferons; liver cirrhosis; liver immunology; macrophages |
Jahrgang: | 11 |
Ausgabe / Heft: | Article 581352 |
Seitenzahl: | 12 |
HeBIS-PPN: | 47751751X |
Institute: | Medizin / Medizin |
DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Lizenz (Deutsch): | Creative Commons - Namensnennung 4.0 |