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An Increase in Epithelial Cell Apoptosis Is Associated with Chronic Intestinal Nematode Infection

Laura J. Cliffe,^1, Christopher S. Potten,² Catherine E. Booth,² and Richard K. Grencis^1*

Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, United Kingdom,¹ Epistem Limited, Incubator Building, 48 Grafton Street, Manchester M13 9XX, United Kingdom²

Received 27 August 2006/ Returned for modification 23 October 2006/ Accepted 10 January 2007

It is well established that homeostasis of the intestinal epithelium becomes dysregulated during gastrointestinal helminth infection and is under immune control. An increase in both enterocyte proliferation and the subsequent generation of crypt hyperplasia are hallmarks of chronic infection with Trichuris muris, a large intestinal dwelling nematode. The effect of this parasitic infection on apoptosis induction in the large intestine and its regulation has been neglected. To address this, mice of resistant and susceptible phenotypes were infected with different doses of T. muris, and the levels of epithelial cell apoptosis were determined. It is clear that apoptosis is induced during chronic T. muris infection. This occurs mainly at the base of the cecal crypt, within the stem cell region. The level of apoptosis induced is independent of worm number, suggesting that it is not a consequence of worm-induced damage but rather a mechanism for controlling cell number within the crypt. Neutralization of both gamma interferon and tumor necrosis factor alpha caused a significant reduction in the levels of apoptosis, showing that proinflammatory cytokines generated in response to chronic infection play an important role in apoptosis induction in this system. It is proposed that the generation of proinflammatory cytokines during chronic T. muris infection may play a positive role, by promoting intestinal epithelial cell apoptosis, to counter infection-induced epithelial hyperplasia.

Published ahead of print on 22 January 2007.

Editor: J. F. Urban, Jr.

Present address: Department of Biochemistry and Molecular Biology, Life Sciences, University of Georgia, Athens, GA 30602.