High constitutive NF-kappaB activity mediates resistance to oxidative stress in neuronal cells.
Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are resistant to oxidative cell death induced by the Alzheimer's disease-associated amyloid beta protein (Abeta) and hydrogen peroxide (H2O2). Here, we show that the transcriptional activity and DNA binding activity of the redox-sensitive transcription factor NF-kappaB and its nuclear expression are constitutively increased in rCl8 cells compared with their nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the transcriptional activity of NF-kappaB in rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct overexpression of a super-repressor mutant form of IkappaBalpha, a specific inhibitor of NF-kappaB, reversed the oxidative stress resistance phenotype of these cells and ultimately led to increased cell death after the challenge with H2O2. Dexamethasone treatment also caused an increase in the protein level of IkappaBalpha. Our data show that an increased baseline of NF-kappaB activity may mediate the resistance of these cells of neuronal origin to oxidative stress. Therefore, the presented model may help to identify possible neuronal target genes of NF-kappaB and to further elucidate the molecular basis of the differential sensitivity of neurons in neurodegenerative conditions associated with an increased oxidative burden, such as in Alzheimer's disease.
Lezoualc'h
F
F
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
Sagara
Y
Y
Holsboer
F
F
Behl
C
C
D000818:Animals; D002135:Calcium-Binding Proteins; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D010641:Phenotype; D051381:Rats; D050857:Synaptotagmins; D014158:Transcription, Genetic
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; C000606206:Nfkbia protein, rat; D050857:Synaptotagmins; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D006861:Hydrogen Peroxide