Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease.
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.
Takeda
Kazuyoshi
K
Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp
Kojima
Yuko
Y
Ikejima
Kenichi
K
Harada
Kenichi
K
Yamashina
Shunhei
S
Okumura
Kyoko
K
Aoyama
Tomonori
T
Frese
Steffen
S
Ikeda
Hiroko
H
Haynes
Nicole M
NM
Cretney
Erika
E
Yagita
Hideo
H
Sueyoshi
Noriyoshi
N
Sato
Nobuhiro
N
Nakanuma
Yasuni
Y
Smyth
Mark J
MJ
Okumura
Ko
K
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000276:immunology*; D045744:Cell Line, Tumor; D002761:Cholangitis / Q000378:metabolism* / Q000473:pathology; D002779:Cholestasis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand