Virchows Archiv

, Volume 473, Issue 1, pp 71–83 | Cite as

Notch inhibition counteracts Paneth cell death in absence of caspase-8

  • M. K. Jeon
  • E. Kaemmerer
  • U. Schneider
  • M. Schiffer
  • C. Klaus
  • J. Hennings
  • T. Clahsen
  • T. Ackerstaff
  • M. Niggemann
  • A. Schippers
  • T. Longerich
  • G. Sellge
  • C. Trautwein
  • N. Wagner
  • C. Liedtke
  • N. Gassler
Original Article


Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.


Caspase 8 Crohn’s disease Notch Paneth cell 




casp8∆int mice

Intestinal casp8 knockout mice




Src homolog region 2-containing protein tyrosine phosphatase 2


Mitogen-activated protein kinase


Receptor-interacting protein 3


Fluorescein isothiocyanate-dextran


Laser microdissected probe


Alcian blue-periodic acid-Schiff reagent



The authors thank P. Akens for typing and proofreading the manuscript.


The work was partially supported by Deutsche Forschungsgemeinschaft (DFG GA 785/5–1) and Deutsche Krebshilfe (GA 109313).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • M. K. Jeon
    • 1
  • E. Kaemmerer
    • 1
    • 2
  • U. Schneider
    • 1
  • M. Schiffer
    • 1
  • C. Klaus
    • 1
  • J. Hennings
    • 3
  • T. Clahsen
    • 2
  • T. Ackerstaff
    • 1
  • M. Niggemann
    • 4
  • A. Schippers
    • 2
  • T. Longerich
    • 1
  • G. Sellge
    • 3
  • C. Trautwein
    • 3
  • N. Wagner
    • 2
  • C. Liedtke
    • 3
  • N. Gassler
    • 1
    • 5
  1. 1.Institute of PathologyRWTH Aachen UniversityAachenGermany
  2. 2.Department of PediatricsRWTH Aachen UniversityAachenGermany
  3. 3.Department of Medicine IIIRWTH Aachen UniversityAachenGermany
  4. 4.Institute of Organic ChemistryRWTH Aachen UniversityAachenGermany
  5. 5.Klinikum BraunschweigInstitute of PathologyBraunschweigGermany

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