Cyclooxygenase-2 prevents Fas-induced liver injury through up-regulation of epidermal growth factor receptor (Hepatology, 2009, 50:834-843)

報告日期: 2009/12/08
報告時間: 15:10/16:00
報告學生: 許晉源
講評老師: 張 玲
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/981208-1.pdf

Cyclooxygenase-2 Prevents Fas-Induced Liver Injury Through Up-Regulation of Epidermal Growth Factor Receptor

 

Guiying Li, Chang Han, Lihong Xu, Kyu Lim, Kumiko Isse, and Tong Wu

HEPATOLOGY 50: 834-843 (2009)

 

Commentator:張玲 教授

Speaker:許晉源

Time: 2009/12/08 1510 - 1600

PlaceRoom 602

 

Abstract:

Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostaglandins (PGs). PGs synthesized increase proliferation, improve angiogenesis, carcinogenesis, and inhibit apoptosis in several tissues. To explore the mechanism of COX-2 in Fas-induced hepatocyte apoptosis and liver failure in vivo, COX-2 transgenic (Tg) and knockout (KO) mouse were generated. This study using the albumin promoter-enhancer–driven vector to generate COX-2 expression in the Tg mice liver. After intraperitoneal injection of anti-mouse Fas monoclonal antibody Jo2 (0.5 μg/g of body weight) for 4 to 6 hours, the COX-2 Tg, COX-2 KO, and wild-type mice of liver injury were examined by serum aminotransferases, histopathology, TUNEL staining, and caspase activity. The COX-2 Tg mice compared to the wild-type mice showed lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, less hepatocyte apoptosis (P<0.01), and less liver damage; this indicated that the COX-2 Tg mice resistance to Fas-induced liver damage. In contrast, the data showed dramatically higher serum AST and ALT, significant hepatocyte apoptosis, and higher levels of caspase-3, caspase-8, and caspase-9 activity in the COX-2 KO mice than the wild-type mice (P < 0.01). The expression levels of epidermal growth factor receptor (EGFR) in the COX-2 Tg mice livers were higher than the wild-type mice; the lowest levels of EGFR expression were observed in the COX-2 KO mice livers. The COX-2 Tg, and wild-type mice were injected intraperitoneally with COX-2 inhibitor (NS-398) or EGFR inhibitor (AG1478) increased Jo2-mediated liver damage and hepatocyte apoptosis. The study showed prevention of Fas-induced hepatocyte apoptosis and liver injury by COX-2 though up-regulation of EGFR.

 

References:

1.   Casado, M., Mollá, B., Martín-Sanz, P., et al. Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes. HEPATOLOGY 45:631-638 (2007).

2.   Pai, R., Soreghan, B., Tarnawski, A. S., et al. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat. Med. 8:289-293 (2002).