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.


CONCLUSIONS
Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction.
Walter
Dorothée
D
Institute of Molecular Medicine and Cell Research, (ZBMZ), Albert Ludwigs University Freiburg, Freiburg, Germany.
Schmich
Kathrin
K
Vogel
Sandra
S
Pick
Robert
R
Kaufmann
Thomas
T
Hochmuth
Florian Christoph
FC
Haber
Angelika
A
Neubert
Karin
K
McNelly
Sabine
S
von Weizsäcker
Fritz
F
Merfort
Irmgard
I
Maurer
Ulrich
U
Strasser
Andreas
A
Borner
Christoph
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D023421:Models, Animal; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494815:Bid protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor; D053148:Caspase 3