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Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes

Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in...

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Autores principales: Gramignoli, Roberto, Ranade, Aarati R., Venkataramanan, Raman, Strom, Stephen C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740548/
https://www.ncbi.nlm.nih.gov/pubmed/36499207
http://dx.doi.org/10.3390/ijms232314880
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author Gramignoli, Roberto
Ranade, Aarati R.
Venkataramanan, Raman
Strom, Stephen C.
author_facet Gramignoli, Roberto
Ranade, Aarati R.
Venkataramanan, Raman
Strom, Stephen C.
author_sort Gramignoli, Roberto
collection PubMed
description Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in urea cycle defects. In cases of sepsis or viral infection, ammonia levels can significantly and abruptly increase in these recipients, erroneously implying rejection. Pro-inflammatory cytokines associated with viral or bacterial infections are known to affect many liver functions, including drug-metabolizing enzymes and hepatic transport activities. We examined the influence of pro-inflammatory cytokines in primary human hepatocytes, isolated from both normal donors or patients with metabolic liver diseases. Different measures of hepatocyte functions, including ammonia metabolism and phase 1–3 metabolism, were performed. All the hepatic functions were profoundly and significantly suppressed after exposure to concentrations of from 0.1 to 10 ng/mL of different inflammatory cytokines, alone and in combination. Our data indicate that, like phase I metabolism, suppression of phase II/III and ammonia metabolism occurs in hepatocytes exposed to pro-inflammatory cytokines in the absence of cell death. Such inflammatory events do not necessarily indicate a rejection response or loss of the cell graft, and these systemic inflammatory signals should be carefully considered when the immunosuppressant regiment is reduced or relieved in a hepatocyte transplantation recipient in response to such alleged rejection.
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spelling pubmed-97405482022-12-11 Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes Gramignoli, Roberto Ranade, Aarati R. Venkataramanan, Raman Strom, Stephen C. Int J Mol Sci Article Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in urea cycle defects. In cases of sepsis or viral infection, ammonia levels can significantly and abruptly increase in these recipients, erroneously implying rejection. Pro-inflammatory cytokines associated with viral or bacterial infections are known to affect many liver functions, including drug-metabolizing enzymes and hepatic transport activities. We examined the influence of pro-inflammatory cytokines in primary human hepatocytes, isolated from both normal donors or patients with metabolic liver diseases. Different measures of hepatocyte functions, including ammonia metabolism and phase 1–3 metabolism, were performed. All the hepatic functions were profoundly and significantly suppressed after exposure to concentrations of from 0.1 to 10 ng/mL of different inflammatory cytokines, alone and in combination. Our data indicate that, like phase I metabolism, suppression of phase II/III and ammonia metabolism occurs in hepatocytes exposed to pro-inflammatory cytokines in the absence of cell death. Such inflammatory events do not necessarily indicate a rejection response or loss of the cell graft, and these systemic inflammatory signals should be carefully considered when the immunosuppressant regiment is reduced or relieved in a hepatocyte transplantation recipient in response to such alleged rejection. MDPI 2022-11-28 /pmc/articles/PMC9740548/ /pubmed/36499207 http://dx.doi.org/10.3390/ijms232314880 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gramignoli, Roberto
Ranade, Aarati R.
Venkataramanan, Raman
Strom, Stephen C.
Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
title Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
title_full Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
title_fullStr Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
title_full_unstemmed Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
title_short Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
title_sort effects of pro-inflammatory cytokines on hepatic metabolism in primary human hepatocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740548/
https://www.ncbi.nlm.nih.gov/pubmed/36499207
http://dx.doi.org/10.3390/ijms232314880
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