Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease

Takeda, Kazuyoshi; Kojima, Yuko; Ikejima, Kenichi; Harada, Kenichi; Yamashina, Shunhei; Okumura, Kyoko; Aoyama, Tomonori; Frese, Steffen; Ikeda, Hiroko; Haynes, Nicole M; Cretney, Erika; Yagita, Hideo; Sueyoshi, Noriyoshi; Sato, Nobuhiro; Nakanuma, Yasuni; Smyth, Mark J; Okumura, Ko (2008). Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 105(31), pp. 10895-900. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.0802702105

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Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosis-inducing ligand (TRAIL) receptor 2/death receptor 5 (DR5) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis.

Item Type:

Journal Article (Original Article)


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

UniBE Contributor:

Frese, Steffen R.






National Academy of Sciences NAS




Factscience Import

Date Deposited:

04 Oct 2013 15:05

Last Modified:

04 May 2014 23:20

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URI: (FactScience: 118349)

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