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Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells
During ischemia or inflammation of organs, intracellular pH can decrease if acid production exceeds buffering capacity. Thus, the microenvironment can expose parenchymal cells to a reduced extracellular pH which can alter pH-dependent intracellular functions. We have previously shown that while sile...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572609/ https://www.ncbi.nlm.nih.gov/pubmed/28884134 http://dx.doi.org/10.1155/2017/1503960 |
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author | Zhang, Zhu-Xu Gan, Ingrid Pavlosky, Alexander Huang, Xuyan Fuhrmann, Benjamin Jevnikar, Anthony M. |
author_facet | Zhang, Zhu-Xu Gan, Ingrid Pavlosky, Alexander Huang, Xuyan Fuhrmann, Benjamin Jevnikar, Anthony M. |
author_sort | Zhang, Zhu-Xu |
collection | PubMed |
description | During ischemia or inflammation of organs, intracellular pH can decrease if acid production exceeds buffering capacity. Thus, the microenvironment can expose parenchymal cells to a reduced extracellular pH which can alter pH-dependent intracellular functions. We have previously shown that while silencing caspase-8 in an in vivo ischemia reperfusion injury (IRI) model results in improved organ function and survival, removal of caspase-8 function in a donor organ can paradoxically result in enhanced receptor-interacting protein kinase 1/3- (RIPK1/3-) regulated necroptosis and accelerated graft loss following transplantation. In our current study, TRAIL- (TNF-related apoptosis-inducing ligand-) induced cell death in vitro at neutral pH and caspase-8 inhibition-enhanced RIPK1-dependent necroptotic death were confirmed. In contrast, both caspase-8 inhibition and RIPK1 inhibition attenuated cell death at a cell pH of 6.7. Cell death was attenuated with mixed lineage kinase domain-like (MLKL) silencing, indicating that MLKL membrane rupture, a distinctive feature of necroptosis, occurs regardless of pH. In summary, there is a distinct regulatory control of apoptosis and necroptosis in endothelial cells at different intracellular pH. These results highlight the complexity of modulating cell death and therapeutic strategies that may need to consider different consequences on cell death dependent on the model. |
format | Online Article Text |
id | pubmed-5572609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-55726092017-09-07 Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells Zhang, Zhu-Xu Gan, Ingrid Pavlosky, Alexander Huang, Xuyan Fuhrmann, Benjamin Jevnikar, Anthony M. J Immunol Res Research Article During ischemia or inflammation of organs, intracellular pH can decrease if acid production exceeds buffering capacity. Thus, the microenvironment can expose parenchymal cells to a reduced extracellular pH which can alter pH-dependent intracellular functions. We have previously shown that while silencing caspase-8 in an in vivo ischemia reperfusion injury (IRI) model results in improved organ function and survival, removal of caspase-8 function in a donor organ can paradoxically result in enhanced receptor-interacting protein kinase 1/3- (RIPK1/3-) regulated necroptosis and accelerated graft loss following transplantation. In our current study, TRAIL- (TNF-related apoptosis-inducing ligand-) induced cell death in vitro at neutral pH and caspase-8 inhibition-enhanced RIPK1-dependent necroptotic death were confirmed. In contrast, both caspase-8 inhibition and RIPK1 inhibition attenuated cell death at a cell pH of 6.7. Cell death was attenuated with mixed lineage kinase domain-like (MLKL) silencing, indicating that MLKL membrane rupture, a distinctive feature of necroptosis, occurs regardless of pH. In summary, there is a distinct regulatory control of apoptosis and necroptosis in endothelial cells at different intracellular pH. These results highlight the complexity of modulating cell death and therapeutic strategies that may need to consider different consequences on cell death dependent on the model. Hindawi 2017 2017-08-13 /pmc/articles/PMC5572609/ /pubmed/28884134 http://dx.doi.org/10.1155/2017/1503960 Text en Copyright © 2017 Zhu-Xu Zhang et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Zhang, Zhu-Xu Gan, Ingrid Pavlosky, Alexander Huang, Xuyan Fuhrmann, Benjamin Jevnikar, Anthony M. Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells |
title | Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells |
title_full | Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells |
title_fullStr | Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells |
title_full_unstemmed | Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells |
title_short | Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells |
title_sort | intracellular ph regulates trail-induced apoptosis and necroptosis in endothelial cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572609/ https://www.ncbi.nlm.nih.gov/pubmed/28884134 http://dx.doi.org/10.1155/2017/1503960 |
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