Specific Deficiency in Nuclear Factor-κB Activation in Neurons of the Central Nervous System

• Published in: Laboratory investigation 2001-09, Vol.81 (9), p.1275-1288
• Main Authors: Jarosinski, Keith W, Whitney, Laurie W, Massa, Paul T
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; Nervous system involvement in other diseases. Miscellaneous; Neurology; Pathology
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3780341

The expression and activation of nuclear factor-κB (NF-κB) in neurons and glia of the central nervous system (CNS) has been intensely investigated because of its potential importance in understanding how this multifunctional transcription factor controls developmental and pathological processes. In particular, there has been interest in how NF-κB may be differentially regulated in these two major functional subgroups of cells in the CNS to provide for specific responses to various stimuli. Of special interest are responses to both proinflammatory cytokines and microbial products that signal from specific cell receptors to activate NF-κB. In the present studies, both neurons and glia (astrocytes) in vivo expressed latent cytoplasmic NF-κB analyzed by immunofluorescence microscopy and electrophoretic mobility shift analysis. In vitro, neurons and astrocytes expressed comparable levels of latent NF-κB molecules, but NF-κB nuclear localization stimulated by proinflammatory cytokines or microbial products was markedly deficient in neurons. In accord with this finding, the rapid degradation of inhibitor of NF-κB alpha (IκBα) that is seen in astrocytes did not occur in neurons in response to these agents. However, long-term exposure to translational inhibitors resulted in IκBα decay and activation of latent NF-κB in neurons, indicating potential NF-κB activity in these cells. Analysis of NF-κB–responsive interferon regulatory factor-1 gene expression indicated that increased nuclear NF-κB in neurons had transcriptional potential. We conclude that mechanisms responsible for inducible targeting of IκBα are uniquely regulated in neurons and account for the hypo-responsiveness of these cells to signals generated during microbial infections in the CNS. Thus, modulation of signals that target IκBα degradation may be unique and a key component of specific NF-κB regulation in neurons.