Kupffer cell-derived cyclooxygenase-2 regulates hepatocyte Bcl-2 expression in choledocho-venous fistula rats.
We have previously demonstrated that after bile duct ligation hepatocytes express Bcl-2, although the mechanisms regulating Bcl-2 expression were not identified. Our aim was to determine if biliary constituents induce hepatocellular expression of Bcl-2 by a cyclooxygenase-2 (COX-2)-dependent mechanism. We used the choledocho-venous fistula (CVF) rat model for these studies and inhibited COX-2 by feeding the animals nimesulide, a selective inhibitor of COX-2 activity. Serum bile acids were 70-fold greater in CVF animals compared with controls, although liver histology and serum alanine aminotransferase values remained normal for the duration of the study. Neither Bcl-2 nor COX-2 was detected in sham-operated animals. However, Bcl-2 was expressed in hepatocytes but not in other liver cells in the CVF animals. In contrast, COX-2 protein was identified in Kupffer cells but not in hepatocytes of CVF animals. Hepatic Bcl-2 protein expression was fourfold lower in the livers from nimesulide-treated CVF rats. In conclusion, high circulating concentrations of biliary constituents are associated with stimulation of de novo hepatocyte expression of Bcl-2 and Kupffer cell expression of COX-2. These data suggest Kupffer cell-derived prostanoids may regulate Bcl-2 expression in the hepatocyte.
Souto
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Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Miyoshi
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Dubois
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Gores
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GJ
D000714:Anastomosis, Surgical; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D002470:Cell Survival; D002478:Cells, Cultured; D003135:Common Bile Duct / Q000502:physiology* / Q000601:surgery; D051546:Cyclooxygenase 2; D005786:Gene Expression Regulation / Q000502:physiology*; D019254:Genes, bcl-2; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D007728:Kupffer Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012082:Renal Veins / Q000601:surgery
D001647:Bile Acids and Salts; D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases