The NF-κB signalling pathway in human diseases: From incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes

Département de Génétique et Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM UR-393, Hôpital Necker, 149 rue de Sèvres, 75743 Paris Cedex 15, France.
Human Molecular Genetics (Impact Factor: 6.39). 11/2002; 11(20):2371-5.
Source: PubMed


The transcription factor NF-kappaB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-kappaB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-kappaB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-kappaB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). The immunological and infectious features observed in patients result from impaired NF-kappaB signalling, including cellular response to LPS, IL-1beta, IL-18, TNF-alpha, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-kappaB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-kappaB signalling pathway.

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Available from: Christine Bodemer, Apr 06, 2014
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    • "Thus, ECEM appears to regulate the inflammatory response by downregulating pro-inflammatory genes, including iNos, Il6, and Cox2. Tnf is also a pro-inflammatory gene upregulated by activation of NF-κB signaling with LPS and other stimuli[35][36]. Interestingly, ECEM exhibited no inhibitory effect on upregulation of Tnf expression in LPS-stimulated RAW cells, whereas ECEM potently suppressed the upregulated expression of iNos, Il6, and Cox2. "

    Full-text · Article · Jan 2015 · Food and Nutrition Sciences
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    • "In most cell types, NF-kB remains bound to IkBα protein and thereby is inactive in the cytoplasm [47,48]. After stimulation by various reagents, IkBα is rapidly phosphorylated by the IkB kinase (IKK) complex and degraded by the proteasome, allowing NF-kB to translocate to the nucleus and activate its target gene [27,49,50]. Thus, NF-kB activates the transcription of many genes capable of suppressing cell death [30]. "
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    ABSTRACT: Background Cimetidine, histamine H2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect. In the testes, peritubular myoid cells and muscle vascular cells death has been associated to seminiferous tubules and testicular microvascularization damages, respectively. Either androgen or histamine H2 receptors have been detected in the mucosa and smooth muscular layer of vas deferens. Thus, the effect of cimetidine on this androgen and histamine-dependent muscular duct was morphologically evaluated. Methods The animals from cimetidine group (CMTG; n=5) received intraperitoneal injections of 100 mg/kg b.w. of cimetidine for 50 days; the control group (CG) received saline solution. The distal portions of vas deferens were fixed in formaldehyde and embedded in paraffin. Masson´s trichrome-stained sections were subjected to morphological and the following morphometrical analyzes: epithelial perimeter and area of the smooth muscular layer. TUNEL (Terminal deoxynucleotidyl-transferase mediated dUTP Nick End Labeling) method, NF-kB (nuclear factor kappa B) and AR (androgen receptors) immunohistochemical detection were also carried out. The birefringent collagen of the muscular layer was quantified in picrosirius red-stained sections under polarized light. The muscular layer was also evaluated under Transmission Electron Microscopy (TEM). Results In CMTG, the mucosa of vas deferens was intensely folded; the epithelial cells showed numerous pyknotic nuclei and the epithelial perimeter and the area of the muscular layer decreased significantly. Numerous TUNEL-labeled nuclei were found either in the epithelial cells, mainly basal cells, or in the smooth muscle cells which also showed typical features of apoptosis under TEM. While an enhanced NF-kB immunoexpression was found in the cytoplasm of muscle cells, a weak AR immunolabeling was detected in these cells. In CMTG, no significant difference was observed in the birefringent collagen content of the muscular layer in comparison to CG. Conclusions Cimetidine induces significant damages in the epithelium; a possible antiandrogenic effect on the basal cells turnover should be considered. The cimetidine-induced muscle cells apoptosis confirms the susceptibility of these cells to this drug. The parallelism between enhanced cytoplasmic NF-kB immunolabeling in the damaged muscular tissue and muscle cell apoptosis suggests that this drug may avoid the translocation of NF-kB to the nucleus and interfere in the control of NF-kB-mediated smooth muscle cell apoptosis. The decreased immunoexpression of ARs verified in the damaged muscular tissue reinforces this possibility.
    Full-text · Article · Apr 2013 · Reproductive Biology and Endocrinology
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    • "As previously described, there is a XLO osteopetrosis, due to mutations of the NEMO (NF-ĸB Essential Modulator) gene, encoding the IκB regulatory subunit of IKK. The mutations described in the only 5 so far known patients cause the replacement of the NEMO stop codon with tryptophan, leading to the addition of 27 irrelevant residues that strongly destabilize the protein (Smahi et al., 2002). All other forms of osteopetrosis, about 30% of patients, still lack of a recognized gene involved and much effort should be made to identify new genes associated with this disease. "

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