Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561

Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany.
Nature (Impact Factor: 41.46). 04/2007; 446(7135):557-61. DOI: 10.1038/nature05698
Source: PubMed


Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease. The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis-acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-kappaB, a master regulator of pro-inflammatory responses, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-kappaB through conditional ablation of NEMO (also called IkappaB kinase-gamma (IKKgamma)) or both IKK1 (IKKalpha) and IKK2 (IKKbeta)-IKK subunits essential for NF-kappaB activation-spontaneously caused severe chronic intestinal inflammation in mice. NF-kappaB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-kappaB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-kappaB signalling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis, and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.

Download full-text


Available from: Deborah L Gumucio
    • "Recent studies have highlighted that epithelial immune dysfunction, especially in Paneth cells, is sufficient to cause chronic intestinal inflammation . Accordingly, intestinal epithelial cell-specific deletion of the NEMO (NF-kB essential modulator) gene, a gene essential for NF-kB signal transduction, resulted in spontaneous, TNF-αdriven apoptosis of intestinal epithelial cells (Nenci et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The intestinal microbiota has important metabolic and host-protective functions. Conversely to these beneficial functions, the intestinal microbiota is thought to play a central role in the etiopathogenesis of inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), a chronic inflammation of the gut mucosa. Genetic screens and studies in experimental mouse models have clearly demonstrated that IBD can develop due to excessive translocation of bacteria into the bowel wall or dysregulated handling of bacteria in genetically susceptible hosts. In healthy individuals, the microbiota is efficiently separated from the mucosal immune system of the gut by the gut barrier, a single layer of highly specialized epithelial cells, some of which are equipped with innate immune functions to prevent or control access of bacterial antigens to the mucosal immune cells. It is currently unclear whether the composition of the microbial flora or individual bacterial strains or pathogens induces or supports the pathogenesis of IBD. Further research will be necessary to carefully dissect the contribution of individual bacterial species to this disease and to ascertain whether specific modulation of the intestinal microbiome may represent a valuable further option for future therapeutic strategies.
    No preview · Article · Aug 2015 · ILAR journal / National Research Council, Institute of Laboratory Animal Resources
  • Source
    • "Gut epithelium is critically involved in the maintenance of intestinal immune homeostasis acting as a physical barrier separating luminal bacteria and immune cells and also expressing antimicrobial peptides. Transcription factor NFí µí¼…B, a master regulator of proinflammatory responses, works in gut epithelial cells in order to control epithelial integrity and the interaction between the mucosal immune system and gut microbiota [1]. Gut epithelial cells have the ability to act as frontline sensors for microbial encounters and to integrate commensal bacteria-derived signals into antimicrobial and immunoregulatory responses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The NF-κB is a transcription factor which plays a key role in regulating biological processes. In response to signals, NF-κB activation occurs via phosphorylation of its inhibitor, which dissociates from the NF-κB dimer allowing the translocation to the nucleus, inducing gene expression. NF-κB activation has direct screening applications for drug discovery for several therapeutic indications. Thus, pathway-specific reporter cell systems appear as useful tools to screen and unravel the mode of action of probiotics and natural and synthetic compounds. Here, we describe the generation, characterization, and validation of human epithelial reporter cell lines for functional studies of NF-κB activation by different pro- and anti-inflammatory agents. Caco-2 and HT-29 cells were transfected with a pNF-κB-hrGFP plasmid which contains the GFP gene under the control of NF-κB binding elements. Three proinflammatory cytokines (TNF- α , IL-1β, and LPS) were able to activate the reporter systems in a dose-response manner, which corresponds to the activation of the NF-κB signaling pathway. Finally, the reporter cell lines were validated using lactic acid bacteria and a natural compound. We have established robust Caco-2-NF-κB-hrGFP and HT-29-NF-κB-hrGFP reporter cell lines which represent a valuable tool for primary screening and identification of bacterial strains and compounds with a potential therapeutic interest.
    Full-text · Article · Apr 2015 · Mediators of Inflammation
  • Source
    • "In this sense, modification of microbiota , inflammation of the gut, and increases in intestinal permeability could mediate or contribute to disease development and metabolic disorders as has been proposed recently [14– 16]. This process evolves with damage to the integrity of the intestinal barrier, causing an increase in bacterial translocation , and therefore an increase in the serum concentration of the external cellular membranes of gram-negative intestinal bacteria, which include lipopolysaccharide (LPS) and result in Toll-like receptor-4-(TLR-4-) mediated inflammatory responses [16] [17] [18]. LPS-induced TLR-4 provokes an inflammatory response through activation of the NF-í µí¼…B signaling pathway and subsequent expression of proinflammatory cytokines such as TNF-í µí»¼ and IL-6 [19] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Maternal intake of trans-fatty acids (TFAs) in the perinatal period triggers a proinflammatory state in offspring. Anthocyanins contained in fruit are promising modulators of inflammation. This study investigated the effect of Jussara supplementation in the maternal diet on the proinflammatory state of the colon in offspring exposed to perinatal TFAs. On the first day of pregnancy rats were divided into four groups: control diet (C), control diet with 0.5% Jussara supplementation (CJ), diet enriched with hydrogenated vegetable fat, rich in TFAs (T), or T diet supplemented with 0.5% Jussara (TJ) during pregnancy and lactation. We showed that Jussara supplementation in maternal diet (CJ and TJ groups) reduced carcass lipid/protein ratios, serum lipids, glucose, IL-6, TNF-α, gene expression of IL-6R, TNF-αR (P < 0.05), TLR-4 (P < 0.01), and increase Lactobacillus spp. (P < 0.05) in the colon of offspring compared to the T group. The IL-10 (P = 0.035) and IL-10/TNF-α ratio (P < 0.01) was higher in the CJ group than in the T group. The 0.5% Jussara supplementation reverses the adverse effects of perinatal TFAs, improving lipid profiles, glucose levels, body composition, and gut microbiota and reducing low-grade inflammation in the colon of 21-day-old offspring, and could contribute to reducing chronic disease development.
    Full-text · Article · Sep 2014 · Mediators of Inflammation
Show more