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a Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité, Berlin, Germany b Department of Clinical Physiology, Campus Benjamin Franklin, Charité, Berlin, Germany
Key Words: apoptosis • barrier function • Crohn's disease • diarrhea • interferon-  • interleukin-13 • tight junctions • TNF- • ulcerative colitis
Address for correspondence: Dr. Joerg D. Schulzke, Charité, Campus Benjamin Franklin, Medizinische Klinik I, Gastroenterology, Infectious Diseases and Rheumatology, Department of Medical Engineering, University of Applied Sciences, Jena, 12200 Berlin, Germany. Voice: +49-30-8445-2666; fax: +49-30-8445-4239. e-mail: Joerg.Schulzke{at}Charite.De
Epithelial barrier function is determined by trans- and paracellular permeabilities, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. The present article aims to present experimental evidence for a functional role of epithelial apoptoses by means of cell culture models as well as in tissues from patients with inflammatory bowel disease. It is shown that epithelial apoptoses are sites of elevated conductance within the intestinal epithelium and that proinflammatory cytokines like TNF-
upregulate both the apoptotic rate and single apoptotic conductivity, making cytokine-induced apoptosis functionally far more relevant than is spontaneous apoptosis. In ulcerative colitis and Crohn's disease (CD), but not in collagenous colitis, apoptotic rates are increased to about 5%, in mild-to-moderately inflamed colon specimens, where as the control apoptotic rate is about 2%. Thus, epithelial apoptoses lead to a loss of ions and water into the intestinal lumen, causing leak flux diarrhea and enabling small antigens of <4,000 Da in the intestinal lumen to enter the intestinal mucosa, thereby perpetuating inflammatory responses. In addition to TNF-, interleukin (IL)-13 is an important inductor of epithelial apoptosis in Th2 immune responses. Therapeutically,TNF--antibodies (infliximab) can restore barrier function in Crohn's disease by downregulating epithelial apoptoses, while epithelial TJs are unaffected.
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