TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality
Nadia Corazza, … , Pascal Schneider, Thomas Brunner
Nadia Corazza, … , Pascal Schneider, Thomas Brunner
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2493-2499. https://doi.org/10.1172/JCI27726.
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Research Article Immunology

TRAIL receptor–mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality

Abstract

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.

Authors

Nadia Corazza, Sabine Jakob, Corinne Schaer, Steffen Frese, Adrian Keogh, Deborah Stroka, Daniela Kassahn, Ralph Torgler, Christoph Mueller, Pascal Schneider, Thomas Brunner

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Figure 6

Bim is required for anti-Fas–induced liver damage.

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Bim is required for anti-Fas–induced liver damage. (A) Wild-type, Bim he...
(A) Wild-type, Bim heterozygous (Bim+/–), Bim homozygous–deficient (Bim–/–), TRAIL-deficient (TRAIL–/–), and TRAIL×Bim double-deficient mice (TRAIL–/–×Bim–/–) were injected with anti-Fas antibody, and serum transaminase levels (AST) were analyzed after 4 hours. Mean values ± SD of 4 mice per group are shown. (B) Histological analysis of liver sections from untreated wild-type mice (Bim+/+) or anti-Fas–treated wild-type and Bim-deficient mice (Bim–/–). Low- and high-power magnification of representative samples is shown. (C) Immunohistochemical detection of active caspase 3 (apoptotic cells, red) in control-treated wild-type mice (Bim+/+) or anti-Fas–treated wild-type or Bim-deficient mice (Bim–/–). (D) Hepatocytes isolated from wild-type (Bim+/+) and Bim-deficient (Bim–/–) mice were pretreated with buffer control or 30 ng/ml TRAIL prior to apoptosis induction with increasing concentrations of soluble Fc-FasL. Mean values ± SD of quadruplicates of 1 representative experiment out of 3 are shown. *P < 0.05, Student’s t test, Bim+/+ with or without TRAIL. (E) Western blot analysis of liver extracts from wild-type, TRAIL-deficient (TRAIL–/–), and Bim-deficient (Bim–/–) mice (2 mice per group). Expression levels of Fas, caspase 8, Bid, BimEL, caspase 3, and JNK as loading control are shown.