Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8


Journal Article

Background & Aims The intestinal epithelium generates a barrier that protects mammals from potentially harmful intestinal contents, such as pathogenic bacteria. Dysregulation of epithelial cell death has been implicated in barrier dysfunction and in the pathogenesis of intestinal inflammation. We investigated mechanisms of cell-death regulation in the intestinal epithelium of mice. Methods Conditional knockout mice (either inducible or permanent) with deletion of cellular FLICE-inhibitory protein (cFlip) or caspase-8 in the intestinal epithelium were analyzed by histology and high-resolution endoscopy. We assessed the effects of cFlip or caspase-8 deficiency on intestinal homeostasis. Results Expression of cFlip in the intestinal epithelium was required for constitutive activation of caspase-8 under steady-state conditions. Intestinal expression of cFlip was required for development; disruption of the gene encoding cFlip from the intestinal epithelium (cFlip fl/fl VillinCre + mice) resulted in embryonic lethality. When cFlip was deleted from the intestinal epithelium of adult mice (cFlip iΔIEC mice), the animals died within a few days from severe tissue destruction, epithelial cell death, and intestinal inflammation. Death of cFlip-depleted intestinal epithelial cells was regulated extrinsically and required the presence of death receptor ligands, such as tumor necrosis factor-α and CD95 ligand, but was independent of receptor-interacting protein 3. cFlip deficiency was associated with strong up-regulation of caspase-8 and caspase-3 activity and excessive apoptosis in intestinal crypts. Conclusions cFlip is required for intestinal tissue homeostasis in mice. It controls the level of activation of caspase-8 to promote survival of intestinal epithelial cells. © 2013 by the AGA Institute.

Full Text

Duke Authors

Cited Authors

  • Wittkopf, N; Günther, C; Martini, E; He, G; Amann, K; He, YW; Schuchmann, M; Neurath, MF; Becker, C

Published Date

  • January 1, 2013

Published In

Volume / Issue

  • 145 / 6

Start / End Page

  • 1369 - 1379

Electronic International Standard Serial Number (EISSN)

  • 1528-0012

International Standard Serial Number (ISSN)

  • 0016-5085

Digital Object Identifier (DOI)

  • 10.1053/j.gastro.2013.08.059

Citation Source

  • Scopus