Journal
MUCOSAL IMMUNOLOGY
Volume 11, Issue 6, Pages 1621-1629Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41385-018-0068-6
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Funding
- DFG collaborative research centers [SFB796, SFB1181, TRR241]
- DFG clinical research units [KFO257, FOR2438]
- Interdisciplinary Centre for Clinical Research (IZKF) of the University Erlangen-Nurnberg
- German Research Foundation DFG [SPP1656, BE3686/2]
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Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation. Moreover vFlip(IEC-tg) mice showed reduced Paneth cell numbers, associated with excessive necrotic cell death. On a molecular level vFlip expression altered classical and alternative NF kappa B activation. Blocking of alternative NF kappa B signaling by deletion of Ikka in vivo largely protected mice from inflammation and Paneth cell loss induced by vFLIP. Collectively, our data provide functional evidence that expression of a single viral protein in IECs can be sufficient to disrupt epithelial homeostasis and to initiate chronic intestinal inflammation.
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