Cyclooxygenase-2 prevents fas-induced liver injury through up-regulation of epidermal growth factor receptor.
Cyclooxygenase-2 (COX-2)-derived prostaglandins participate in a number of pathophysiological responses such as inflammation, carcinogenesis, and modulation of cell growth and survival. This study used complementary approaches of COX-2 transgenic (Tg) and knockout (KO) mouse models to evaluate the mechanism of COX-2 in Fas-induced hepatocyte apoptosis and liver failure in vivo. We generated Tg mice with targeted expression of COX-2 in the liver by using the albumin promoter-enhancer-driven vector. The COX-2 Tg, COX-2 KO, and wild-type mice were treated with the anti-Fas antibody Jo2 (0.5 microg/g of body weight) for 4 to 6 hours, and the extent of liver injury was assessed by histopathology, serum aminotransferases, TUNEL staining, and caspase activation. The COX-2 Tg mice showed resistance to Fas-induced liver injury in comparison with the wild-type mice; this was reflected by the lower alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, less liver damage, and less hepatocyte apoptosis (P < 0.01). In contrast, the COX-2 KO mice showed significantly higher serum ALT and AST levels, more prominent hepatocyte apoptosis, and higher levels of caspase-8, caspase-9, and caspase-3 activity than the wild-type mice (P < 0.01). The COX-2 Tg livers expressed higher levels of epidermal growth factor receptor (EGFR) than the wild-type controls; the COX-2 KO livers expressed the lowest levels of EGFR. Pretreatment with a COX-2 inhibitor (NS-398) or an EGFR inhibitor (AG1478) exacerbated Jo2-mediated liver injury and hepatocyte apoptosis.


CONCLUSIONS
These findings demonstrate that COX-2 prevents Fas-induced hepatocyte apoptosis and liver failure at least in part through up-regulation of EGFR.
Li
Guiying
G
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Han
Chang
C
Xu
Lihong
L
Lim
Kyu
K
Isse
Kumiko
K
Wu
Tong
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis*; D053200:Fas-Associated Death Domain Protein / Q000502:physiology; D022781:Hepatocytes / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009578:Nitrobenzenes / Q000494:pharmacology; D011799:Quinazolines; D013449:Sulfonamides / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation; D019014:fas Receptor
D053200:Fas-Associated Death Domain Protein; D009578:Nitrobenzenes; D011799:Quinazolines; D013449:Sulfonamides; D020032:Tyrphostins; D019014:fas Receptor; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C101044:RTKI cpd; D051546:Cyclooxygenase 2; D066246:ErbB Receptors