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

Corazza, Nadia; Jakob, Sabine; Schaer, Corinne; Frese, Steffen; Keogh, Adrian; Stroka, Deborah; Kassahn, Daniela; Torgler, Ralph; Mueller, Christoph; Schneider, Pascal; Brunner, Thomas (2006). TRAIL receptor-mediated JNK activation and Bim phosphorylation critically regulate Fas-mediated liver damage and lethality. Journal of clinical investigation, 116(9), pp. 2493-9. Ann Arbor, Mich.: American Society for Clinical Investigation 10.1172/JCI27726

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery

UniBE Contributor:

Corazza, Nadia; Frese, Steffen R.; Müller, Christoph and Brunner, Thomas

ISSN:

0021-9738

ISBN:

16955144

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:47

Last Modified:

22 Jul 2015 10:00

Publisher DOI:

10.1172/JCI27726

PubMed ID:

16955144

Web of Science ID:

000240380700025

BORIS DOI:

10.7892/boris.19336

URI:

https://boris.unibe.ch/id/eprint/19336 (FactScience: 1872)

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