ROS-production-mediated activation of AP-1 but not NFkappaB inhibits glutamate-induced HT4 neuronal cell death.
Aside from their deleterious effect, reactive oxygen species (ROS) can function as small messenger molecules during physiologic processes. ROS have been shown to activate the transcription nuclear factor kappa B (NFkappaB) and activator protein 1 (AP-1). Exposure of HT4 neuronal cells to 10 mM glutamate results in cell death after 12 h. Here we show that glutamate treatment leads to an increase in ROS production and activation of AP-1, but not NFkappaB. 12-O-Tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C and an inducer of NFkappaB and AP-1, protected the cells. This protective effect was preceded by increased production of ROS compared with glutamate alone, which was accompanied by a synergistic increase in AP-1, but not NFkappaB activity. We used all-trans-retinoic acid (ATRA), overexpression of retinoic acid receptor alpha (RARalpha) and a decoy oligonucleotide inclusion assay to suppress AP-1 activity. NFkappaB was inhibited by using a super suppressor (IkappaBalphaDeltaN-transfected cells). Inhibition of AP-1, but not NFkappaB resulted in increased cellular vulnerability to glutamate. Inhibition of AP-1 activity was coincident with a decrease in ROS production. Thus, although ROS are significant to the cell-death effect induced by glutamate, they also activate protective pathways mediated by increasing AP-1 activity, and not that of NFkappaB.
Aharoni-Simon
Michal
M
The School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Israel.
Reifen
Ram
R
Tirosh
Oren
O
D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D005544:Forecasting; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000494:pharmacology* / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010957:Plasmids; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D018698:Glutamic Acid; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate