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Dual TNF alpha-Induced Effects on NRF2 Mediated Antioxidant Defence in Astrocyte-Rich Cultures: Role of Protein Kinase Activation
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- Correa, Fernando (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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- Mallard, Carina, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
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- Nilsson, Michael, 1962 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap och rehabilitering,Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
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- (creator_code:org_t)
- 2012-09-02
- 2012
- English.
- In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 37:12, s. 2842-2855
- Journal article (peer-reviewed)
Abstract
Subject headings
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- Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic molecule that can have both protective and detrimental effects in neurodegeneration. Here we have investigated the temporal effects of TNF alpha on the inducible Nrf2 system in astrocyte-rich cultures by determination of glutathione (GSH) levels, gamma glutamylcysteine ligase (gamma GCL) activity, the protein levels of Nrf2, Keap1, the catalytic and modulatory subunit of gamma GCL (gamma GCL-C and gamma GCL-M respectively). Astrocyte-rich cultures were exposed for 24 or 72 h to different concentrations of TNF alpha. Acute exposure (24 h) of astrocyte-rich cultures to 10 ng/mL of TNF alpha increased GSH, gamma GCL activity, the protein levels of gamma GCL-M, gamma GCL-C and Nrf2 in parallel with decreased levels of Keap1. Antioxidant responsive element (ARE)-mediated transcription was blocked by inhibitors of ERK1/2, JNK and Akt whereas inactivation of p38 and GSK3 beta further enhanced transcription. In contrast treatment with TNF alpha for 72 h decreased components of the Nrf2 system in parallel with an increase of Keap1. Stimulation of the Nrf2 system by tBHQ was intact after 24 h but blocked after 72 h treatment with TNF alpha. This down-regulation after 72 h correlated with activation of p38 MAPK and GSK3 beta, since inhibition of these signalling pathways reversed this effect. The upregulation of the Nrf2 system by TNF alpha (24 h treatment) protected the cells from oxidative stress through elevated gamma GCL activity whereas the down-regulation (72 h treatment) caused pronounced oxidative toxicity. One of the important implications of the results is that in a situation where Nrf2 is decreased, such as in Alzheimer's disease, the effect of TNF alpha is detrimental.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Biomedicinsk laboratorievetenskap/teknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Biomedical Laboratory Science/Technology (hsv//eng)
Keyword
- Neuroinflammation
- Nrf2
- Antioxidant system
- TNF alpha
- Glutathione
- transcription factor nrf2
- necrosis-factor-alpha
- gamma-glutamylcysteine
- synthetase
- oxidative stress
- gene-expression
- p38 mapk
- proinflammatory
- cytokines
- coordinate regulation
- cell-survival
- brain
- eng b
- 1994
- neuron
- v12
- p139
Publication and Content Type
- ref (subject category)
- art (subject category)
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