Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation

Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-κB pathway

Lara Marchetti, Matthias Klein, K. Schlett, Klaus Pfizenmaier, Ulrich L M Eisel

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303 Citations (Scopus)

Abstract

We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1-/- mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2-/- neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-κB (NF-κB) activation were apparent upon TNF treatment. Both TNFR1 and TNFK2 induced the NF-κB pathway, yet with distinguishable Kinetics and upstream activating components, TNFK1 only induced transient NF-κB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-κB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-D-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-κB activation by TNFK2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-κB activity was essential for neuronal survival. Thus, the duration of NF-κB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFKs.

Original languageEnglish
Pages (from-to)32869-32881
Number of pages13
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
Publication statusPublished - Jul 30 2004

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Phosphatidylinositol 3-Kinase
Receptors, Tumor Necrosis Factor, Type II
N-Methyl-D-Aspartate Receptors
Glutamic Acid
Tumor Necrosis Factor-alpha
Chemical activation
Receptors, Tumor Necrosis Factor, Type I
Neurons
Signal Transduction
Proto-Oncogene Proteins c-akt
Tumor Necrosis Factor Receptors
Transgenic Mice
Neurotransmitter Agents
Neuroprotection
Apoptosis
Kinetics
Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

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abstract = "We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1-/- mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2-/- neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-κB (NF-κB) activation were apparent upon TNF treatment. Both TNFR1 and TNFK2 induced the NF-κB pathway, yet with distinguishable Kinetics and upstream activating components, TNFK1 only induced transient NF-κB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-κB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-D-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-κB activation by TNFK2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-κB activity was essential for neuronal survival. Thus, the duration of NF-κB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFKs.",
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AU - Klein, Matthias

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AU - Pfizenmaier, Klaus

AU - Eisel, Ulrich L M

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N2 - We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1-/- mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2-/- neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-κB (NF-κB) activation were apparent upon TNF treatment. Both TNFR1 and TNFK2 induced the NF-κB pathway, yet with distinguishable Kinetics and upstream activating components, TNFK1 only induced transient NF-κB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-κB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-D-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-κB activation by TNFK2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-κB activity was essential for neuronal survival. Thus, the duration of NF-κB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFKs.

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