1. Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany
2. EMBL Mouse Biology Unit, I-00016 Monterotondo, Italy
3. Laboratory of Clinical Immunology, I. Department of Medicine, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany
4. Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Viale Manzoni 56, 20089 Rozzano, Milan, Italy
5. Department of Cell & Developmental Biology, Center for Organogenesis, The University of Michigan, Ann Arbor, Michigan 48109-0616, USA
6. These authors contributed equally to this work.

Correspondence to: Manolis Pasparakis^1,2 Correspondence and requests for materials should be addressed to M.P. (Email: pasparakis@uni-koeln.de).

Abstract

Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease^{1, 2, 3, 4}. 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^{3, 5, 6}. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-B, a master regulator of pro-inflammatory responses^{7, 8}, 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-B through conditional ablation of NEMO (also called IB kinase- (IKK)) or both IKK1 (IKK) and IKK2 (IKK)—IKK subunits essential for NF-B activation^{7, 8, 9}—spontaneously caused severe chronic intestinal inflammation in mice. NF-B 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-B signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-B 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.

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