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

Publication ,  Journal Article
Wittkopf, N; Günther, C; Martini, E; He, G; Amann, K; He, YW; Schuchmann, M; Neurath, MF; Becker, C
Published in: Gastroenterology
January 1, 2013

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 (cFlipfl/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.

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Published In

Gastroenterology

DOI

EISSN

1528-0012

ISSN

0016-5085

Publication Date

January 1, 2013

Volume

145

Issue

6

Start / End Page

1369 / 1379

Related Subject Headings

  • Gastroenterology & Hepatology
  • 3210 Nutrition and dietetics
  • 3202 Clinical sciences
  • 1114 Paediatrics and Reproductive Medicine
  • 1109 Neurosciences
  • 1103 Clinical Sciences
 

Citation

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Wittkopf, N., Günther, C., Martini, E., He, G., Amann, K., He, Y. W., … Becker, C. (2013). Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology, 145(6), 1369–1379. https://doi.org/10.1053/j.gastro.2013.08.059
Wittkopf, N., C. Günther, E. Martini, G. He, K. Amann, Y. W. He, M. Schuchmann, M. F. Neurath, and C. Becker. “Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8.” Gastroenterology 145, no. 6 (January 1, 2013): 1369–79. https://doi.org/10.1053/j.gastro.2013.08.059.
Wittkopf N, Günther C, Martini E, He G, Amann K, He YW, et al. Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology. 2013 Jan 1;145(6):1369–79.
Wittkopf, N., et al. “Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8.” Gastroenterology, vol. 145, no. 6, Jan. 2013, pp. 1369–79. Scopus, doi:10.1053/j.gastro.2013.08.059.
Wittkopf N, Günther C, Martini E, He G, Amann K, He YW, Schuchmann M, Neurath MF, Becker C. Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology. 2013 Jan 1;145(6):1369–1379.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

ISSN

0016-5085

Publication Date

January 1, 2013

Volume

145

Issue

6

Start / End Page

1369 / 1379

Related Subject Headings

  • Gastroenterology & Hepatology
  • 3210 Nutrition and dietetics
  • 3202 Clinical sciences
  • 1114 Paediatrics and Reproductive Medicine
  • 1109 Neurosciences
  • 1103 Clinical Sciences