Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.

<h4>Background</h4>Hypoxia and hypoxia-reoxygenation (H-R) are pathogenic factors in many liver diseases that lead to hepatocyte death as a result of reactive oxygen species (ROS) accumulation. The tumor necrosis factor super-family member CD154 can also induce hepatocyte apoptosis via a...

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Autores principales:	Ricky H Bhogal, Christopher J Weston, Stuart M Curbishley, David H Adams, Simon C Afford
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/17497c0d1e01473a9d1a767b1e5c62e5
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spelling	oai:doaj.org-article:17497c0d1e01473a9d1a767b1e5c62e52021-11-18T07:29:18ZActivation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.1932-620310.1371/journal.pone.0030867https://doaj.org/article/17497c0d1e01473a9d1a767b1e5c62e52012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22295117/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Hypoxia and hypoxia-reoxygenation (H-R) are pathogenic factors in many liver diseases that lead to hepatocyte death as a result of reactive oxygen species (ROS) accumulation. The tumor necrosis factor super-family member CD154 can also induce hepatocyte apoptosis via activation of its receptor CD40 and induction of autocrine/paracrine Fas Ligand/CD178 but the relationship between CD40 activation, ROS generation and apoptosis is poorly understood. We hypothesised that CD40 activation and ROS accumulation act synergistically to drive human hepatocyte apoptosis.<h4>Methods</h4>Human hepatocytes were isolated from liver tissue and exposed to an in vitro model of hypoxia and H-R in the presence or absence of CD154 and/or various inhibitors. Hepatocyte ROS production, apoptosis and necrosis were determined by labelling cells with 2',7'-dichlorofluorescin, Annexin-V and 7-AAD respectively in a three-colour reporter flow cytometry assay.<h4>Results</h4>Exposure of human hepatocytes to recombinant CD154 or platelet-derived soluble CD154 augments ROS accumulation during H-R resulting in NADPH oxidase-dependent apoptosis and necrosis. The inhibition of c-Jun N-terminal Kinase and p38 attenuated CD154-mediated apoptosis but not necrosis.<h4>Conclusions</h4>CD154-mediated apoptosis of hepatocytes involves ROS generation that is amplified during hypoxia-reoxygenation. This finding provides a molecular mechanism to explain the role of platelets in hepatocyte death during ischemia-reperfusion injury.Ricky H BhogalChristopher J WestonStuart M CurbishleyDavid H AdamsSimon C AffordPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30867 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ricky H Bhogal Christopher J Weston Stuart M Curbishley David H Adams Simon C Afford Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
description	<h4>Background</h4>Hypoxia and hypoxia-reoxygenation (H-R) are pathogenic factors in many liver diseases that lead to hepatocyte death as a result of reactive oxygen species (ROS) accumulation. The tumor necrosis factor super-family member CD154 can also induce hepatocyte apoptosis via activation of its receptor CD40 and induction of autocrine/paracrine Fas Ligand/CD178 but the relationship between CD40 activation, ROS generation and apoptosis is poorly understood. We hypothesised that CD40 activation and ROS accumulation act synergistically to drive human hepatocyte apoptosis.<h4>Methods</h4>Human hepatocytes were isolated from liver tissue and exposed to an in vitro model of hypoxia and H-R in the presence or absence of CD154 and/or various inhibitors. Hepatocyte ROS production, apoptosis and necrosis were determined by labelling cells with 2',7'-dichlorofluorescin, Annexin-V and 7-AAD respectively in a three-colour reporter flow cytometry assay.<h4>Results</h4>Exposure of human hepatocytes to recombinant CD154 or platelet-derived soluble CD154 augments ROS accumulation during H-R resulting in NADPH oxidase-dependent apoptosis and necrosis. The inhibition of c-Jun N-terminal Kinase and p38 attenuated CD154-mediated apoptosis but not necrosis.<h4>Conclusions</h4>CD154-mediated apoptosis of hepatocytes involves ROS generation that is amplified during hypoxia-reoxygenation. This finding provides a molecular mechanism to explain the role of platelets in hepatocyte death during ischemia-reperfusion injury.
format	article
author	Ricky H Bhogal Christopher J Weston Stuart M Curbishley David H Adams Simon C Afford
author_facet	Ricky H Bhogal Christopher J Weston Stuart M Curbishley David H Adams Simon C Afford
author_sort	Ricky H Bhogal
title	Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
title_short	Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
title_full	Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
title_fullStr	Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
title_full_unstemmed	Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
title_sort	activation of cd40 with platelet derived cd154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/17497c0d1e01473a9d1a767b1e5c62e5
work_keys_str_mv	AT rickyhbhogal activationofcd40withplateletderivedcd154promotesreactiveoxygenspeciesdependentdeathofhumanhepatocytesduringhypoxiaandreoxygenation AT christopherjweston activationofcd40withplateletderivedcd154promotesreactiveoxygenspeciesdependentdeathofhumanhepatocytesduringhypoxiaandreoxygenation AT stuartmcurbishley activationofcd40withplateletderivedcd154promotesreactiveoxygenspeciesdependentdeathofhumanhepatocytesduringhypoxiaandreoxygenation AT davidhadams activationofcd40withplateletderivedcd154promotesreactiveoxygenspeciesdependentdeathofhumanhepatocytesduringhypoxiaandreoxygenation AT simoncafford activationofcd40withplateletderivedcd154promotesreactiveoxygenspeciesdependentdeathofhumanhepatocytesduringhypoxiaandreoxygenation
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Activation of CD40 with platelet derived CD154 promotes reactive oxygen species dependent death of human hepatocytes during hypoxia and reoxygenation.

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