TY  - JOUR
A1  - Rüschenbaum, Sabrina
A1  - Cai, Chengcong
A1  - Schmidt, Matthias
A1  - Schwarzkopf, Katharina
A1  - Dittmer, Ulf
A1  - Zeuzem, Stefan
A1  - Welsch, Christoph
A1  - Lange, Christian Michael
T1  - Translation of IRF-1 restricts hepatic interleukin-7 production to types I and II interferons: implications for hepatic immunity
T2  - Frontiers in immunology
N2  - 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.
KW  - liver immunology
KW  - macrophages
KW  - cytokines
KW  - interferons
KW  - inflammation
KW  - liver cirrhosis
KW  - acute-on-chronic liver failure
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57435
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-574356
SN  - 1664-3224
VL  - 11
IS  - Article 581352
PB  - Frontiers Media
CY  - Lausanne
ER  -