Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes


Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNFalpha/ActD)-induced apoptosis. Conclusion: Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction.


Projects: HepatoSys

Hepatology 48(6): 1942-53
13th Nov 2008

Dorothée Walter, Kathrin Schmich, Sandra Vogel, Robert Pick, Thomas Kaufmann, Florian Christoph Hochmuth, Angelika Haber, Karin Neubert, Sabine McNelly, Fritz von Weizsäcker, Irmgard Merfort, Ulrich Maurer, Andreas Strasser, Christoph Borner

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[Irmgard Merfort] [Christoph Borner] [Sabine Mac Nelly]

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Views: 2548
  • Created: 30th Aug 2012 at 12:31
  • Last updated: 24th Oct 2013 at 16:22

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