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(American Journal of Pathology. 2005;166:1671-1680.)
© 2005 American Society for Investigative Pathology

Tannic Acid Inhibits Cholangiocyte Proliferation after Bile Duct Ligation via a Cyclic Adenosine 5',3'-Monophosphate-Dependent Pathway

Silvia Taffetani*, Yoshiyuki Ueno{dagger}, Fanyin Meng*, Julie Venter{ddagger}, Heather Francis*, Shannon Glaser*, Gianfranco Alpini*{ddagger}§ and Tushar Patel*

From the Departments of Internal Medicine* and Medical Physiology,{ddagger} Texas A&M University System Health Science Center College of Medicine, and Scott and White Clinic, Temple, Texas; the Central Texas Veterans Health Care System,§ Temple, Texas; and the Division of Gastroenterology,{dagger} Tohoku University School of Medicine, Aobaku, Sendai, Japan

Chronic cholestatic diseases are characterized by morphological changes involving cholangiocyte proliferation and functional alterations of secretory capacity. The plant polyphenol tannic acid inhibits the growth of malignant human cholangiocytes. However, the mechanisms by which tannic acid limits excessive cholangiocyte proliferation are unknown. In this study we assessed the effect of tannic acid on cholangiocyte proliferation after bile duct ligation in rats. Tannic acid feeding decreased cholangiocyte proliferation and ductal mass in vivo after bile duct ligation. These changes were associated with functional changes in bile secretion and with decreases of intracellular cyclic adenosine 5',3'-monophosphate. The anti-proliferative effect of tannic acid was associated with a reduction of ERK1,2 phosphorylation. Additionally, tannic acid feeding decreased protein kinase A phosphorylation and activity. Similar changes were observed in isolated cholangiocytes during in vitro incubation with tannic acid. Furthermore, forskolin abolished the anti-proliferative effect of tannic acid on cholangiocyte proliferation after bile duct ligation. In conclusion, the anti-proliferative effects of tannic acid in cholangiocytes involve modulation of ERK1,2 by a cyclic adenosine 5',3'-monophosphate-protein kinase A-dependent pathway. These data suggest that tannic acid may be useful in limiting excessive cholangiocyte proliferation and modulating secretion during cholestasis.






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Copyright © 2005 by the American Society for Investigative Pathology.