Mechanism of glial activation by S100B: involvement of the transcription factor NF kappa B

Compelling evidence links chronic activation of glia and the subsequent cyc le of neuroinflammation and neuronal dysfunction to the progression of neur odegeneration in disorders such as Alzheimer's disease (AD). S100B, a glial -derived cytokine, is significantly elevated in the brains of AD patients a nd high concentrations of SlOOB are believed to be detrimental to brain fun ction. As a first step toward elucidating the mechanisms by which SlOOB mig ht be serving this detrimental role, we examined the mechanisms by which S1 00B stimulates glial inducible nitric oxide synthase (iNOS), an oxidative s tress related enzyme that has been linked to neuropathology through the pro duction of neurotoxic peroxynitrite. We report here that S100B stimulates i NOS in rat primary cortical astrocytes through a signal transduction pathwa y that involves activation of the transcription factor NF kappaB. NTF kappa B activation was demonstrated by nuclear translocation of the p65 NF kappaB subunit, stimulation of NF kappaB-specific DNA binding activity, and stimu lation of NF kappaB-dependent transcriptional activity. Furthermore, S100B- induced iNOS promoter activation was inhibited upon mutation of the NF kapp aB 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 whi ch S100B activation of glia could participate in the generation of oxidativ e stress in the brain. (C) 2001 Elsevier Science Inc. All rights reserved.