Crohn's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Crohn's Disease, including details on symptoms, diagnosis, treatment, causes, medication. | ||||||
|
Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C Department of Medicine 1, Friedrich-Alexander-University, D-91054 Erlangen, Germany. Dysfunction of the intestinal epithelium is believed to result in the excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease, an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides, which hamper access and survival of bacteria adjacent to the epithelium. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn's disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death. Published 16 September 2011 in Nature, 477(7364): 335-9. Articles on Crohn's Disease published 1 September 2011: Cord colitis syndrome in cord-blood stem-cell transplantation. N Engl J Med, 365(9): 815-24. Articles on Crohn's Disease published 19 August 2011: Aspirin in the aetiology of Crohn's disease and ulcerative colitis: a European prospective cohort study. Aliment Pharmacol Ther, 34(6): 649-55. Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. Rheumatology (Oxford), 50(9): 1700-11. Articles on Crohn's Disease published 15 August 2011: Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease. Biochem Pharmacol, 82(7): 737-45. Current epidemiological and experimental studies support a beneficial role of dietary polyphenols in several gastrointestinal diseases, including inflammatory bowel disease. The aim of this study was to gain a better understanding of the effects of a naturally occurring polyphenol, ellagic acid, present in some fruits such as pomegranate, raspberries and nuts among others, in an experimental murine model of Crohn's disease by intra-colonic administration of TNBS in rats. Analysis of the lesions ... [Abstract] [Full-text] Articles on Crohn's Disease published 12 August 2011: Complete genome sequence of the Crohn's disease-associated adherent-invasive Escherichia coli strain HM605. J Bacteriol, 193(17): 4540. Adherent-invasive Escherichia coli strains are increasingly being associated with intestinal pathologies. Here we present the genome sequence of E. coli HM605, a strain isolated from colonic biopsy specimens of a patient with Crohn's disease. [Abstract] [Full-text] Articles on Crohn's Disease published 10 August 2011: Occurrence of Crohn's disease in children after total colectomy for ulcerative colitis. J Surg Res, 170(1): 38-40. Articles on Crohn's Disease published 8 August 2011: Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology, 141(2): 633-41. Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut, 60(9): 1229-35. © 2004-2011 Crohn's Disease Research Today. All Rights Reserved. |
| ||||
