Journal
NEUROBIOLOGY OF AGING
Volume 22, Issue 5, Pages 765-772Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0197-4580(01)00233-0
Keywords
glia; S100B; NF kappa B; iNOS; Alzheimer's disease; cytokine; nitric oxide; astrocyte
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Funding
- NIA NIH HHS [AG13939, AG00260] Funding Source: Medline
- NIGMS NIH HHS [GM08152, GM08061] Funding Source: Medline
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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 SlOOB are believed to be detrimental to brain function. As a first step toward elucidating the mechanisms by which SlOOB 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 NF kappaB. NTF kappaB activation was demonstrated by nuclear translocation of the p65 NF kappaB subunit, stimulation of NF kappaB-specific DNA binding activity, and stimulation of NF kappaB-dependent transcriptional activity. Furthermore, S100B-induced iNOS promoter activation was inhibited upon mutation of the NF kappaB response element in the promoter, and transfection of cells with an NTF kappaB 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. (C) 2001 Elsevier Science Inc. All rights reserved.
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