Activation of NF-κB by Reactive Oxygen Intermediates in the Nervous System

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Abstract
Nuclear factor kappa B (NF-κB) is a transcription factor crucially involved in glial and neuronal function. NF-κB is ubiquitously distributed within the nervous system, and its inducible activity can be discerned from constitutive activity. Prototypic inducible NF-κB in the nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory IκB-α molecule. A number of signals from the cell surface can lead to rapid activation of NK-κB, thus releasing the inhibition by IκB. This activates translocation of NF-κB to the nucleus, where it binds to κB motifs of target genes and activates transcription. Previous findings have identified reactive oxygen intermediates (ROI) as a common denominator of NF-κB activating signals. More specifically, hydrogen peroxide (H2O2) might be used as second messenger in the NF-κB system, despite its cytotoxicity. Analysis of pathways leading to NF-κB activation in the nervous system has identified a number of ROI-dependent pathways such as cytokine- and neurotrophin-mediated activation, glutamatergic signal transduction, and various diseases with crucial ROI involvement (e.g., Alzheimer's disease, Parkinson's disease, experimental autoimmune encephalomyelitis, multiple sclerosis, amyotrophic lateral sclerosis, and injury). A number of NF-κB-specific target genes contribute to the production of ROI or are involved in detoxification of ROIs. In this review, possible mechanisms and regulatory pathways of ROI-mediated NF-κB activation are discussed.