NF-κB-related genetic diseases

Abstract

The recent identification of genetic diseases (incontinentia pigmenti, anhidrotic ectodermal dysplasia with immunodeficiency and cylindromatosis) resulting from mutations affecting components of the nuclear factor-jB (NF-jB) signaling pathway provides a unique opportunity to understand the function of NF-jB in vivo. Besides confirming the importance of NF-jB in innate and acquired immunity or bone mass control, analysis of these diseases has uncovered new critical roles played by this transcription factor in the development and homeostasis of the epidermis and the proper function of lymphatic vessels. In addition, the identified mutations will help understanding at the molecular level how NF-jB is activated in response to cell stimulation.

Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance

“…The prosurvival activity of NF-kB also plays a key role in a wide range of other biological processes, including maturation of B and T lymphocytes (Hayden and Ghosh, 2004;Bottero et al, 2006;Claudio et al, 2006), innate and adaptive immunity (Weil and Israe¨l, 2006), bone morphogenesis epidermal homeostasis, hair follicle development, and neuronal development and function (Kucharczak et al, 2003;Mattson and Meffert, 2006). When deregulated, NF-kB-mediated suppression of PCD also participates in the pathogenesis of widespread human diseases, including various cancers -where it promotes transformation, tumor progression and resistance to anticancer therapy (Brasseres and Baldwin, 2006;Dutta et al, 2006; see also Kucharczak et al, 2003;Karin, 2006;Kim et al, 2006) -chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), various inherited conditions, and metabolic and vascular disorders such as type-II diabetes and atherosclerosis (Kucharczak et al, 2003;Kumar et al, 2004;Courtois and Smahi, 2006;Perkins and Gilmore, 2006). As discussed below, it is plausible that the pathogenetic role that NF-kB plays in these diseases is owed, at least in part, to an inappropriate control of ROS activity.…”

“…Disturbances in the NF-kB-imposed suppression of TNF-R-induced killing play a central role in the pathogenesis of a wide spectrum of human diseases (Kucharczak et al, 2003, Kumar et al, 2004Courtois and Smahi, 2006;Karin, 2006;Kim et al, 2006;Papa et al, 2006). In some of these diseases, the pathogenetic action of NF-kB appears to involve a deregulation of ROS and JNK activities.…”

“…The relevance of the control that NF-kB exerts on ROS and JNK signaling is likely to extend to other conditions in which these activities may play a significant pathogenetic role, such as other inflammatory diseases, sepsis, ischemia/reperfusion injury, and cardiovascular and neuro-degenerative diseases, including Parkinson's and Alzheimer's diseases (Haddad, 2002;Kumar et al, 2004;Victor et al, 2004;Mattson and Meffert, 2006). Finally, an NF-kB-dependent deregulation of the ROS/JNK pathway may contribute to the pathogenesis of certain hereditary disorders characterized by either impaired or exaggerated NF-kB activity and, consequently, an imbalance in cell survival (Courtois and Smahi, 2006;Papa et al, 2006).…”

“…This negative control that NF-kB exerts on ROS formation appears to be especially crucial for the suppression of PCD induced by the proinflammatory cytokine tumor necrosis factor (TNF)a and perhaps other stimuli (Sakon et al, 2003;Pham et al, 2004;Kamata et al, 2005;Papa et al, 2006). In addition to antagonism of TNFa-induced PCD, the prosurvival action of NF-kB is essential for B and T lymphopoiesis, bone morphogenesis and pathogenesis of widespread human diseases, ranging from cancer and chronic inflammation to vascular and metabolic disorders (Kucharczak et al, 2003;Greten and Karin, 2004;Kumar et al, 2004;Bottero et al, 2006;Courtois and Smahi, 2006;Karin, 2006;Kim et al, 2006;Papa et al, 2006). Thus, ROS appear to be at an obligatory crossroads of opposing pathways for life and death elicited by the engagement of TNF receptors (TNF-Rs) and, most likely, other triggers.…”

“…The different aspects of the regulation and functions of NF-kB-family transcription factors and their role in control of PCD are the subject of other articles in this issue (Dutta et al, 2006;Gilmore, 2006;Perkins, 2006;Scheidereit, 2006) and of excellent reviews previously published elsewhere (Gerondakis and Strasser, 2003;Kucharczak et al, 2003;Hayden and Ghosh, 2004;Bottero et al, 2006;Claudio et al, 2006;Courtois and Smahi, 2006;Karin, 2006;Kim et al, 2006;Mattson and Meffert, 2006;Perkins and Gilmore, 2006) Here, we focus on recent discoveries that have unveiled how NF-kB and ROS engage in a mutual cross-talk. Specifically, we discuss the status of our current understanding of the basis for involvement of ROS in activation of NF-kB, and the mechanisms underlying the negative control that NF-kB exerts on these species and, ultimately, PCD.…”