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Cell Signal. 2014 Mar;26(3):512-20. doi: 10.1016/j.cellsig.2013.11.029. Epub 2013 Dec 2.

Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway.

Author information

1
Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy. Electronic address: m.qaisiya@csf.units.it.
2
Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy. Electronic address: carlos.zabetta@csf.units.it.
3
Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy. Electronic address: cristina.bellarosa@csf.units.it.
4
Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy; Department of Medical Sciences, University of Trieste, 34100 Trieste, Italy. Electronic address: ctliver@csf.units.it.

Abstract

Unconjugated bilirubin (UCB) is responsible for neonatal jaundice and high level of free bilirubin (Bf) can lead to kernicterus. Previous studies suggest that oxidative stress is a critical component of UCB-induced neurotoxicity. The Nrf2 pathway is a powerful sensor for cellular redox state and is activated directly by oxidative stress and/or indirectly by stress response protein kinases. Activated Nrf2 translocates to nucleus, binds to Antioxidant Response Element (ARE), and enhances the up-regulation of cytoprotective genes that mediate cell survival. The aim of the present study was to investigate the role of Nrf2 pathway in cell response to bilirubin mediated oxidative stress in the neuroblastoma SH-SY5Y cell line. Cells exposed to a toxic concentration of UCB (140 nM Bf) showed an increased intracellular ROS levels and enhanced nuclear accumulation of Nrf2 protein. UCB stimulated transcriptional induction of ARE-GFP reporter gene and induced mRNA expression of multiple antioxidant response genes as: xCT, Gly1, γGCL-m, γGCL-c, HO-1, NQO1, FTH, ME1, and ATF3. Nrf2 siRNA decreased UCB induced mRNA expression of HO1 (75%), NQO1 (54%), and FTH (40%). The Nrf2-related HO-1 induction was reduced to 60% in cells pre-treated with antioxidant (NAC) or specific signaling pathway inhibitors for PKC, P38α and MEK1/2 (80, 40 and 25%, respectively). In conclusion, we demonstrated that SH-SY5Y cells undergo an adaptive response against UCB-mediated oxidative stress by activation of multiple antioxidant response, in part through Nrf2 pathway.

KEYWORDS:

ARE; ATF3; Antioxidant Response Element; Bf; Bilirubin neurotoxicity; FTH; GSH; Gly1; HO-1; Heme oxygenase 1; JNK; MAPK; ME1; N-acetylcystein; NAC; NADPH quinone oxidoreductase 1; NF-E2 related factor 2; NQO1; Nrf2; Nrf2 pathway; OS; Oxidative stress; PERK; PI3K; PKC; ROS; Stress response protein kinases; UCB; activating transcription factor 3; c-Jun NH2-terminal kinases; cystine/glutamate exchanger system; cytosolic malic enzyme 1; eIF2α; eukaryotic translation initiation factor 2α; ferritin heavy chain; free bilirubin; glutathione; glycine up-take transporter; heme oxygenase 1; mitogen-activated protein kinase; oxidative stress; phosphatidylinositide 3-kinases; protein kinase C; protein kinase-like endoplasmic reticulum kinase; reactive oxygen species; tBHQ; tertiary-butylhydroquinone; unconjugated bilirubin; xCT; γ-GCL-c; γ-GCL-m; γ-glutamylcysteine synthetase, catalytic subunit; γ-glutamylcysteine synthetase, modulatory subunit

PMID:
24308969
DOI:
10.1016/j.cellsig.2013.11.029
[Indexed for MEDLINE]

Publication type, MeSH terms, Substances, Grant support

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