The IκB/NF-κB system: a key determinant of mucosal inflammation and protection

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Abstract
The ubiquitous transcription factor NF-κB is a central regulator of the transcriptional activation of a number of genes involved in cell adhesion, immune and proinflammatory responses, apoptosis, differentiation, and growth. Induction of these genes in intestinal epithelial cells (IECs) by activated NF-κB profoundly influences mucosal inflammation and repair. NF-κB activation requires the removal of IκB from NF-κB by inducible proteolysis, which liberates this transcription factor for migration to the nucleus, where it binds to κB-regulatory elements and induces transcription. IκBα degradation is incomplete and delayed in IECs, resulting in buffered responses to luminal stimuli. The stimulatory environment partially determines whether the effect of NF-κB is protective or deleterious for the host. κB-dependent proinflammatory gene expression, particularly chemokines, major histocompatibility complex class II antigens, and adhesion molecules may be extremely important in early protective responses to mucosal pathogens but, when dysregulated, could lead to the development of chronic inflammation, as seen in inflammatory bowel diseases. The key role of NF-κB in regulating expression of a number of proinflammatory genes makes this protein an attractive target for selective therapeutic intervention.