Dual TNFα-Induced Effects on NRF2 Mediated Antioxidant Defence in Astrocyte-Rich Cultures: Role of Protein Kinase Activation

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• 作者：Fernando Correa (1)
  Carina Mallard (2)
  Michael Nilsson (3)
  Mats Sandberg (1)
  
• 关键词：Neuroinflammation ; Nrf2 ; Antioxidant system ; TNFα ; Glutathione
• 刊名：Neurochemical Research
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：37
• 期：12
• 页码：2842-2855
• 全文大小：630KB
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• 作者单位：Fernando Correa (1)
  Carina Mallard (2)
  Michael Nilsson (3)
  Mats Sandberg (1)
  
  1. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, PO BOX 420, 405 30, G?teborg, Sweden
  2. Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, G?teborg, Sweden
  3. Institute of Neuroscience and Physiology, CBR, University of Gothenburg, G?teborg, Sweden
  
• ISSN：1573-6903

文摘

Tumor necrosis factor-α (TNFα) is a pleiotropic molecule that can have both protective and detrimental effects in neurodegeneration. Here we have investigated the temporal effects of TNFα on the inducible Nrf2 system in astrocyte-rich cultures by determination of glutathione (GSH) levels, γglutamylcysteine ligase (γGCL) activity, the protein levels of Nrf2, Keap1, the catalytic and modulatory subunit of γGCL (γGCL-C and γGCL-M respectively). Astrocyte-rich cultures were exposed for 24 or 72?h to different concentrations of TNFα. Acute exposure (24?h) of astrocyte-rich cultures to 10?ng/mL of TNFα increased GSH, γGCL activity, the protein levels of γGCL-M, γGCL-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 GSK3β further enhanced transcription. In contrast treatment with TNFα 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 TNFα. This down-regulation after 72?h correlated with activation of p38 MAPK and GSK3β, since inhibition of these signalling pathways reversed this effect. The upregulation of the Nrf2 system by TNFα (24?h treatment) protected the cells from oxidative stress through elevated γGCL 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 TNFα is detrimental.