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

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2012 Sep 4

PMID 22941452

Citations 9

Authors

Fernando Correa

Carina Mallard

Michael Nilsson

Mats Sandberg

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The citrus flavonoid "Nobiletin" impedes STZ-induced Alzheimer's disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism.

El-Maraghy S, Reda A, Essam R, Kortam M Inflammopharmacology. 2023; 31(5):2701-2717.

PMID: 37598127 PMC: 10518278. DOI: 10.1007/s10787-023-01292-z.

Quercetin Exhibits α7nAChR/Nrf2/HO-1-Mediated Neuroprotection Against STZ-Induced Mitochondrial Toxicity and Cognitive Impairments in Experimental Rodents.

Singh N, Garabadu D Neurotox Res. 2021; 39(6):1859-1879.

PMID: 34554409 DOI: 10.1007/s12640-021-00410-5.

The Role of Mitochondrial and Endoplasmic Reticulum Reactive Oxygen Species Production in Models of Perinatal Brain Injury.

Singh-Mallah G, Nair S, Sandberg M, Mallard C, Hagberg H Antioxid Redox Signal. 2019; 31(9):643-663.

PMID: 30957515 PMC: 6657303. DOI: 10.1089/ars.2019.7779.

The reciprocal interplay between TNFα and the circadian clock impacts on cell proliferation and migration in Hodgkin lymphoma cells.

Abreu M, Basti A, Genov N, Mazzoccoli G, Relogio A Sci Rep. 2018; 8(1):11474.

PMID: 30065253 PMC: 6068144. DOI: 10.1038/s41598-018-29847-z.

Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress.

McLaughlin J, Paris J, Mintzopoulos D, Hymel K, Kim J, Cirino T Biol Psychiatry Cogn Neurosci Neuroimaging. 2017; 2(7):599-609.

PMID: 29057370 PMC: 5648358. DOI: 10.1016/j.bpsc.2017.04.002.

References

Dringen R, Pfeiffer B, Hamprecht B . Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci. 1999; 19(2):562-9. PMC: 6782200. View

Goven D, Boutten A, Lecon-Malas V, Boczkowski J, Bonay M . Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK. FEBS Lett. 2009; 583(21):3508-18. DOI: 10.1016/j.febslet.2009.10.010. View

Shen G, Hebbar V, Nair S, Xu C, Li W, Lin W . Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein. J Biol Chem. 2004; 279(22):23052-60. DOI: 10.1074/jbc.M401368200. View

Fiore M, Angelucci F, Alleva E, Branchi I, Probert L, Aloe L . Learning performances, brain NGF distribution and NPY levels in transgenic mice expressing TNF-alpha. Behav Brain Res. 2000; 112(1-2):165-75. DOI: 10.1016/s0166-4328(00)00180-7. View

Cui J, Shao L, Young L, Wang J . Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience. 2006; 144(4):1447-53. DOI: 10.1016/j.neuroscience.2006.11.010. View

Shih A, Johnson D, Wong G, Kraft A, Jiang L, Erb H . Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci. 2003; 23(8):3394-406. PMC: 6742304. View

Yu M, Li H, Liu Q, Liu F, Tang L, Li C . Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal. 2011; 23(5):883-92. DOI: 10.1016/j.cellsig.2011.01.014. View

Song I, Tatebe S, Dai W, Kuo M . Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. J Biol Chem. 2005; 280(31):28230-40. DOI: 10.1074/jbc.M413103200. View

Hansson E . Cellular composition of a cerebral hemisphere primary culture. Neurochem Res. 1984; 9(2):153-72. DOI: 10.1007/BF00964164. View

10.

McCoy M, Tansey M . TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation. 2008; 5:45. PMC: 2577641. DOI: 10.1186/1742-2094-5-45. View

11.

Yu R, Chen C, Mo Y, Hebbar V, Owuor E, Tan T . Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J Biol Chem. 2000; 275(51):39907-13. DOI: 10.1074/jbc.M004037200. View

12.

Yoon K, Jung E, Lee S . TRAF6-mediated regulation of the PI3 kinase (PI3K)-Akt-GSK3beta cascade is required for TNF-induced cell survival. Biochem Biophys Res Commun. 2008; 371(1):118-21. DOI: 10.1016/j.bbrc.2008.04.007. View

13.

Figiel I . Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain. Acta Neurobiol Exp (Wars). 2008; 68(4):526-34. DOI: 10.55782/ane-2008-1720. View

14.

Morales A, Garcia-Ruiz C, Miranda M, Mari M, Colell A, Ardite E . Tumor necrosis factor increases hepatocellular glutathione by transcriptional regulation of the heavy subunit chain of gamma-glutamylcysteine synthetase. J Biol Chem. 1997; 272(48):30371-9. DOI: 10.1074/jbc.272.48.30371. View

15.

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

16.

Niture S, Jaiswal A . INrf2 (Keap1) targets Bcl-2 degradation and controls cellular apoptosis. Cell Death Differ. 2010; 18(3):439-51. PMC: 3010499. DOI: 10.1038/cdd.2010.114. View

17.

Zhao Z, Chen Y, Wang J, Sternberg P, Freeman M, Grossniklaus H . Age-related retinopathy in NRF2-deficient mice. PLoS One. 2011; 6(4):e19456. PMC: 3084871. DOI: 10.1371/journal.pone.0019456. View

18.

Brywe K, Mallard C, Gustavsson M, Hedtjarn M, Leverin A, Wang X . IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?. Eur J Neurosci. 2005; 21(6):1489-502. DOI: 10.1111/j.1460-9568.2005.03982.x. View

19.

De Lella Ezcurra A, Chertoff M, Ferrari C, Graciarena M, Pitossi F . Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiol Dis. 2009; 37(3):630-40. DOI: 10.1016/j.nbd.2009.11.018. View

20.

Perry S, Dewhurst S, Bellizzi M, Gelbard H . Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk?. J Neurovirol. 2002; 8(6):611-24. PMC: 7094979. DOI: 10.1080/13550280290101021. View