Area Editoriale
Deregulation ofintestinal immune responses seems to have a principal function in thepathogenesis of inflammatory bowel disease. The gut epithelium is criticallyinvolved in the maintenance of intestinal immune homeostasis-acting as aphysical barrier separating luminal bacteria and immune cells, and alsoexpressing antimicrobial peptides. However, the molecular mechanisms thatcontrol this function of gut epithelial cells are poorly understood. Here weshow that the transcription factor NF-kappaB, a master regulator ofpro-inflammatory responses, functions in gut epithelial cells to controlepithelial integrity and the interaction between the mucosal immune system andgut microflora. Intestinal epithelial-cell-specific inhibition of NF-kappaBthrough conditional ablation of NEMO (also called IkappaB kinase-gamma(IKKgamma)) or both IKK1 (IKKalpha) and IKK2 (IKKbeta)-IKK subunits essentialfor NF-kappaB activation-spontaneously caused severe chronic intestinalinflammation in mice. NF-kappaB deficiency led to apoptosis of colonicepithelial cells, impaired expression of antimicrobial peptides and translocationof bacteria into the mucosa. Concurrently, this epithelial defect triggered achronic inflammatory response in the colon, initially dominated by innateimmune cells but later also involving T lymphocytes. Deficiency of the geneencoding the adaptor protein MyD88 prevented the development of intestinalinflammation, demonstrating that Toll-like receptor activation by intestinalbacteria is essential for disease pathogenesis in this mouse model.Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosisfactor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibitedintestinal inflammation, demonstrating that TNF receptor-1 signalling iscrucial for disease induction. These findings demonstrate that a primaryNF-kappaB signalling defect in intestinal epithelial cells disrupts immunehomeostasis in the gastrointestinal tract, causing aninflammatory-bowel-disease-like phenotype. Our results identify NF-kappaBsignalling in the gut epithelium as a critical regulator of epithelialintegrity and intestinal immune homeostasis, and have important implicationsfor understanding the mechanisms controlling the pathogenesis of humaninflammatory bowel disease. Leggil'articolo