Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism
Acid sphingomyelinase (ASMase) and NF-κB participate in tumor necrosis factor α (TNFα) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-κB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selec...
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Format: | Article |
Language: | English |
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Elsevier
2002-10-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996102905309 |
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doaj-2f6ede74064f466f849ab9db1ab61c02 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
ZaiFang Yu Guanjun Cheng Xiaoming Wen Gary D. Wu Wang-Tso Lee David Pleasure |
spellingShingle |
ZaiFang Yu Guanjun Cheng Xiaoming Wen Gary D. Wu Wang-Tso Lee David Pleasure Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism Neurobiology of Disease acid sphingomyelinase AMPA receptor neuronal excitotoxicity NF-κB tumor necrosis factor α |
author_facet |
ZaiFang Yu Guanjun Cheng Xiaoming Wen Gary D. Wu Wang-Tso Lee David Pleasure |
author_sort |
ZaiFang Yu |
title |
Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism |
title_short |
Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism |
title_full |
Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism |
title_fullStr |
Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism |
title_full_unstemmed |
Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent Mechanism |
title_sort |
tumor necrosis factor α increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the ampa–glutamate receptor subunit glur1 via an acid sphingomyelinase- and nf-κb-dependent mechanism |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2002-10-01 |
description |
Acid sphingomyelinase (ASMase) and NF-κB participate in tumor necrosis factor α (TNFα) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-κB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-κB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFα. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-κB p50. We conclude that TNFα can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-κB-dependent mechanism. TNFα levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFα signal transduction will diminish neuronal necrosis in these diseases. |
topic |
acid sphingomyelinase AMPA receptor neuronal excitotoxicity NF-κB tumor necrosis factor α |
url |
http://www.sciencedirect.com/science/article/pii/S0969996102905309 |
work_keys_str_mv |
AT zaifangyu tumornecrosisfactoraincreasesneuronalvulnerabilitytoexcitotoxicnecrosisbyinducingexpressionoftheampaglutamatereceptorsubunitglur1viaanacidsphingomyelinaseandnfkbdependentmechanism AT guanjuncheng tumornecrosisfactoraincreasesneuronalvulnerabilitytoexcitotoxicnecrosisbyinducingexpressionoftheampaglutamatereceptorsubunitglur1viaanacidsphingomyelinaseandnfkbdependentmechanism AT xiaomingwen tumornecrosisfactoraincreasesneuronalvulnerabilitytoexcitotoxicnecrosisbyinducingexpressionoftheampaglutamatereceptorsubunitglur1viaanacidsphingomyelinaseandnfkbdependentmechanism AT garydwu tumornecrosisfactoraincreasesneuronalvulnerabilitytoexcitotoxicnecrosisbyinducingexpressionoftheampaglutamatereceptorsubunitglur1viaanacidsphingomyelinaseandnfkbdependentmechanism AT wangtsolee tumornecrosisfactoraincreasesneuronalvulnerabilitytoexcitotoxicnecrosisbyinducingexpressionoftheampaglutamatereceptorsubunitglur1viaanacidsphingomyelinaseandnfkbdependentmechanism AT davidpleasure tumornecrosisfactoraincreasesneuronalvulnerabilitytoexcitotoxicnecrosisbyinducingexpressionoftheampaglutamatereceptorsubunitglur1viaanacidsphingomyelinaseandnfkbdependentmechanism |
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spelling |
doaj-2f6ede74064f466f849ab9db1ab61c022021-03-20T04:48:04ZengElsevierNeurobiology of Disease1095-953X2002-10-01111199213Tumor Necrosis Factor α Increases Neuronal Vulnerability to Excitotoxic Necrosis by Inducing Expression of the AMPA–Glutamate Receptor Subunit GluR1 via an Acid Sphingomyelinase- and NF-κB-Dependent MechanismZaiFang Yu0Guanjun Cheng1Xiaoming Wen2Gary D. Wu3Wang-Tso Lee4David Pleasure5Department of Neurology Research, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Internal Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104Department of Neurology Research, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Internal Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104Department of Neurology Research, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Internal Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104Department of Neurology Research, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Internal Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104Department of Neurology Research, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Internal Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104Department of Neurology Research, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Pharmacology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104; Department of Internal Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104Acid sphingomyelinase (ASMase) and NF-κB participate in tumor necrosis factor α (TNFα) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-κB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-κB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFα. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-κB p50. We conclude that TNFα can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-κB-dependent mechanism. TNFα levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFα signal transduction will diminish neuronal necrosis in these diseases.http://www.sciencedirect.com/science/article/pii/S0969996102905309acid sphingomyelinaseAMPA receptorneuronal excitotoxicityNF-κBtumor necrosis factor α |