On the TRAIL towards understanding the cause(s) of PSC

[Guest guest]

Proc. Natl. Acad. Sci. U.S.A. [in press] (2008)

Death receptor 5 mediated-apoptosis contributes to cholestatic liver

disease.

Takeda K, Kojima Y, Ikejima K, Harada K, Yamashina S, Okumura K,

Aoyama T, Frese S, Ikeda H, Haynes NM, Cretney E, Yagita H, Sueyoshi

N, Sato N, Nakanuma Y, Smyth MJ, Okumura K

Abstract

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.

Key words: cholangitis primary sclerosing cholangitis

Dave

(father of (23); PSC 07/03; UC 08/03)