Recent advances towards understanding redox mechanisms in the activation of nuclear factor κB

The transcription factor, nuclear factor-kappa B (NF-kappa B) has been studied extensively due to its prominent role in the regulation of immune and inflammatory genes, apoptosis, and cell proliferation. It has been known for more that a decade that NF-kappa B is a redox-sensitive transcription factor. The contribution of redox regulation and the location of potential redox-sensitive sites within the NF-kappa B activation pathway are subject to intense debate due to many conflicting reports. Redox regulation of NF-kappa B has been extensively addressed in this journal and the reader is referred to two comprehensive reviews on the subject [1,2]. With the identification of signaling intermediates proximal to the degradation of the inhibitor, I kappa B, the number of potential redox-sensitive sites is rapidly increasing. The purpose of this review is to address recent insights into the NF-kappa B signaling cascades that an triggered by proinflammatory cytokines such as TNF-alpha and IL-1 beta. In addition, the role of nitrogen monoxide ((NO)-N-.) in the regulation of NF-kappa B will be reviewed. Opportunities for redox regulation that occur upstream of I kappa B-alpha degradation, as well as the potential for redox control of phosphorylation of NF-kappa B subunits, will be discussed. Redox-sensitive steps are likely to depend on the nature of the NF-kappa B activator, the type of reactive oxygen or nitrogen species involved, the selectivity of signaling pathways activated, as well as the cell type under investigation. Lastly, it is discussed how redox regulation of NF-kappa B activation is likely to involve multiple subcellular compartments. (C) 2000 Elsevier Science Inc.