Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury.
Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Lu
L
Yao
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Weina
W
Chen
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Chang
C
Han
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana twu@tulane.edu.
Tong
T
Wu
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000633:toxicity; D017209:Apoptosis; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000276:immunology; D022781:Hepatocytes / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000906:Antibodies; D053222:Fas Ligand Protein; D051057:Proto-Oncogene Proteins c-akt; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse
Akt; Jo2; PGE2; liver injury; mPGES-1