Mechanism of glial activation by S100B: involvement of the transcription factor NFkappaB.
Compelling evidence links chronic activation of glia and the subsequent cycle of neuroinflammation and neuronal dysfunction to the progression of neurodegeneration in disorders such as Alzheimer's disease (AD). S100B, a glial-derived cytokine, is significantly elevated in the brains of AD patients and high concentrations of S100B are believed to be detrimental to brain function. As a first step toward elucidating the mechanisms by which S100B might be serving this detrimental role, we examined the mechanisms by which S100B stimulates glial inducible nitric oxide synthase (iNOS), an oxidative stress related enzyme that has been linked to neuropathology through the production of neurotoxic peroxynitrite. We report here that S100B stimulates iNOS in rat primary cortical astrocytes through a signal transduction pathway that involves activation of the transcription factor NFkappaB. NFkappaB activation was demonstrated by nuclear translocation of the p65 NFkappaB subunit, stimulation of NFkappaB-specific DNA binding activity, and stimulation of NFkappaB-dependent transcriptional activity. Furthermore, S100B-induced iNOS promoter activation was inhibited upon mutation of the NFkappaB response element in the promoter, and transfection of cells with an NFkappaB inhibitor blocked S100B-induced iNOS promoter activation and nitric oxide production. These studies define a signal transduction pathway by which S100B activation of glia could participate in the generation of oxidative stress in the brain.
Lam
A G
AG
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA.
Koppal
T
T
Akama
K T
KT
Guo
L
L
Craft
J M
JM
Samy
B
B
Schavocky
J P
JP
Watterson
D M
DM
Van Eldik
L J
LJ
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000276:immunology; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D014158:Transcription, Genetic / Q000187:drug effects
D002135:Calcium-Binding Proteins; D016328:NF-kappa B; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat