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

ZaiFang Yu, Guanjun Cheng, Xiaoming Wen, Gary D. Wu, Wang Tso Lee, David E Pleasure

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)199-213
Number of pages15
JournalNeurobiology of Disease
Volume11
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Sphingomyelin Phosphodiesterase
AMPA Receptors
Glutamate Receptors
Necrosis
Tumor Necrosis Factor-alpha
Acids
Kainic Acid
Neurons
Signal Transduction
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Central Nervous System Diseases
Protein Subunits
Brain Ischemia
Knockout Mice
Ischemia
Genes

Keywords

  • Acid sphingomyelinase
  • AMPA receptor
  • Neuronal excitotoxicity
  • NF-κB
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Neurology

Cite this

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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",
abstract = "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.",
keywords = "Acid sphingomyelinase, AMPA receptor, Neuronal excitotoxicity, NF-κB, Tumor necrosis factor α",
author = "ZaiFang Yu and Guanjun Cheng and Xiaoming Wen and Wu, {Gary D.} and Lee, {Wang Tso} and Pleasure, {David E}",
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T1 - 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

AU - Yu, ZaiFang

AU - Cheng, Guanjun

AU - Wen, Xiaoming

AU - Wu, Gary D.

AU - Lee, Wang Tso

AU - Pleasure, David E

PY - 2002

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AB - 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.

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