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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 wel...

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Autores principales: Rueschenbaum, Sabrina, Cai, Chengcong, Schmidt, Matthias, Schwarzkopf, Katharina, Dittmer, Ulf, Zeuzem, Stefan, Welsch, Christoph, Lange, Christian M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874116/
https://www.ncbi.nlm.nih.gov/pubmed/33584648
http://dx.doi.org/10.3389/fimmu.2020.581352
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author Rueschenbaum, Sabrina
Cai, Chengcong
Schmidt, Matthias
Schwarzkopf, Katharina
Dittmer, Ulf
Zeuzem, Stefan
Welsch, Christoph
Lange, Christian M.
author_facet Rueschenbaum, Sabrina
Cai, Chengcong
Schmidt, Matthias
Schwarzkopf, Katharina
Dittmer, Ulf
Zeuzem, Stefan
Welsch, Christoph
Lange, Christian M.
author_sort Rueschenbaum, Sabrina
collection PubMed
description 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.
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spelling pubmed-78741162021-02-11 Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity Rueschenbaum, Sabrina Cai, Chengcong Schmidt, Matthias Schwarzkopf, Katharina Dittmer, Ulf Zeuzem, Stefan Welsch, Christoph Lange, Christian M. Front Immunol Immunology 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. Frontiers Media S.A. 2021-01-14 /pmc/articles/PMC7874116/ /pubmed/33584648 http://dx.doi.org/10.3389/fimmu.2020.581352 Text en Copyright © 2021 Rueschenbaum, Cai, Schmidt, Schwarzkopf, Dittmer, Zeuzem, Welsch and Lange http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Rueschenbaum, Sabrina
Cai, Chengcong
Schmidt, Matthias
Schwarzkopf, Katharina
Dittmer, Ulf
Zeuzem, Stefan
Welsch, Christoph
Lange, Christian M.
Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity
title Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity
title_full Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity
title_fullStr Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity
title_full_unstemmed Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity
title_short Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity
title_sort translation of irf-1 restricts hepatic interleukin-7 production to types i and ii interferons: implications for hepatic immunity
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874116/
https://www.ncbi.nlm.nih.gov/pubmed/33584648
http://dx.doi.org/10.3389/fimmu.2020.581352
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