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

Günther C, Martini E, He G, Amann KU, He YW, Neurath M, Becker C (2013)

Publication Language: English

Publication Status: Published

Publication Type: Journal article

Publication year: 2013

Journal

Gastroenterology Elsevier

Book Volume: 145

Pages Range: 1369-79

Journal Issue: 6

DOI: 10.1053/j.gastro.2013.08.059

Abstract

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.\nConditional 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.\nExpression 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.\ncFlip is required for intestinal tissue homeostasis in mice. It controls the level of activation of caspase-8 to promote survival of intestinal epithelial cells.\nBACKGROUND & AIMS\nMETHODS\nRESULTS\nCONCLUSIONS

Authors with CRIS profile

Claudia Günther Professur für Gastrointestinale Pathophysiologie Eva Liebing Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Guiwei He Lehrstuhl für Genetik Kerstin Ute Amann Department of Nephropathology Markus Neurath Lehrstuhl für Innere Medizin I Christoph Becker Professur für Molekulare Gastroenterologie

Involved external institutions

Duke University US United States (USA) (US)

How to cite

APA:

Günther, C., Martini, E., He, G., Amann, K.U., He, Y.-W., Neurath, M., & Becker, C. (2013). Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology, 145(6), 1369-79. https://doi.org/10.1053/j.gastro.2013.08.059

MLA:

Günther, Claudia, et al. "Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8." Gastroenterology 145.6 (2013): 1369-79.

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