NF-kappa B in cardiovascular disease - Diverse and specific effects of a general transcription factor?

The transcription factor NF-kappa B regulates a wide variety of biological effects in diverse cell types and organs, particularly stress and adaptive responses. Recently, it has become recognized that NF-kappa B and its upstream regulator tumor necrosis factor (TNF)-alpha regulate specific antithetical effects. For instance, in the heart, NF-kappa B has been found to be required for development of late preconditioning against myocardial infarction and yet is critically involved in mediating cell death after ischemia/reperfusion injury. There remains a bias that NF-kappa B is a general transcription factor that is activated by a plethora of stimuli, including neurohormonal, pathophysiological, and stress stimuli, and affects regulation of numerous downstream genes. The question has become, how can such a general transcription factor be critically involved in mediating specific effects? An emerging hypothesis is that NF-kappa B is part of a complicated signaling network or web, and that different combinatorial interactions between various activated signaling pathway components produce specific outcomes. This idea is supported by the large number of interactions discovered in the past 14 years between NF-kappa B and other signaling pathways at multiple levels. Notwithstanding the complexities of signal-induced activation of NF-kappa B, since it is a transcription factor, specific effects of NF-kappa B activation must be underlain by the activation and/or suppression of distinct subsets of NF-kappa B-dependent genes. At this level, selectivity is conferred by the expression of specific NF-kappa B subunits, their post translational modifications, and by combinatorial interactions between NF-kappa B and other transcription factors and co-activators that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-kappa B-dependent transcriptional network. Understanding how the overall cellular signaling network translates NF-kappa B activation into the regulation of specific subsets of NF-kappa B-dependent genes will lead to a mechanistic understanding of how NF-kappa B mediates diverse and paradoxical biological effects. In addition to the experimental approaches that have been historically undertaken, modern proteomic, genomic, and computational modeling approaches need to be applied in an integrated manner to achieve a workable understanding of NF-kappa B regulation and the NF-kappa B-dependent transcriptional network. Since NF-kappa B is activated in association with disease and contributes functionally to pathophysiology, understanding the detailed mechanisms by which the seemingly generalized activation of NF-kappa B results in specific effects will allow us to identify particular signaling modules, transcriptional co-factors, protein complexes, and the discrete sets of NF-kappa B-dependent genes involved in specific effects. Certain of these may prove to be even better therapeutic targets than NF-kappa B, allowing us to block the injurious effects while preserving the potentially beneficial effects of adaptive signaling in the heart.