TRAIL receptor-mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality.
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with potent apoptosis-inducing properties in tumor cells. In particular, TRAIL strongly synergizes with conventional chemotherapeutic drugs to induce tumor cell death. Thus, TRAIL has been proposed as a promising future cancer therapy. Little, however, is known regarding what the role of TRAIL is in normal untransformed cells and whether therapeutic administration of TRAIL, alone or in combination with other apoptotic triggers, may cause tissue damage. In this study, we investigated the role of TRAIL in Fas-induced (CD95/Apo-1-induced) hepatocyte apoptosis and liver damage. While TRAIL alone failed to induce apoptosis in isolated murine hepatocytes, it strongly amplified Fas-induced cell death. Importantly, endogenous TRAIL was found to critically regulate anti-Fas antibody-induced hepatocyte apoptosis, liver damage, and associated lethality in vivo. TRAIL enhanced anti-Fas-induced hepatocyte apoptosis through the activation of JNK and its downstream substrate, the proapoptotic Bcl-2 homolog Bim. Consistently, TRAIL- and Bim-deficient mice and wild-type mice treated with a JNK inhibitor were protected against anti-Fas-induced liver damage. We conclude that TRAIL and Bim are important response modifiers of hepatocyte apoptosis and identify liver damage and lethality as a possible risk of TRAIL-based tumor therapy.
Corazza
Nadia
N
Division of Immunopathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Jakob
Sabine
S
Schaer
Corinne
C
Frese
Steffen
S
Keogh
Adrian
A
Stroka
Deborah
D
Kassahn
Daniela
D
Torgler
Ralph
R
Mueller
Christoph
C
Schneider
Pascal
P
Brunner
Thomas
T
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D003433:Crosses, Genetic; D004789:Enzyme Activation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics*; D019014:fas Receptor / Q000633:toxicity*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D048670:MAP Kinase Kinase 4