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Am J Physiol Gastrointest Liver Physiol 294: G506-G519, 2008. First published December 20, 2007; doi:10.1152/ajpgi.00304.2007
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LIVER AND BILIARY TRACT

Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation

Sharon DeMorrow,1,2 Heather Francis,1 Eugenio Gaudio,3 Yoshiyuki Ueno,4 Julie Venter,5 Paolo Onori,5 Antonio Franchitto,3 Bradley Vaculin,6 Shelley Vaculin,7 and Gianfranco Alpini2,6,7

1Division of Research and Education, Scott & White Hospital, Temple; 2Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; 3Division of Anatomy, University "La Sapienza", Rome, Italy; 4Division of Gastroenterology, Tohoku University Hospital, Aobaku, Sendai, Japan; 5Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; 6Systems Biology and Translational Medicine, The Texas A&M University System Health Science Center, College of Medicine, Temple; and 7Division of Research, Central Texas Veterans Health Care System, Temple, Texas

Submitted 6 July 2007 ; accepted in final form 16 December 2007

The endocannabinoid system regulates various aspects of hepatic fibrosis; however, nothing is known about its role in regulating cholangiocyte proliferation and function. We evaluated the effects of anandamide (AEA) on cholangiocyte proliferation and explored the effects of AEA on the thioredoxin 1 (TRX1)/redox factor 1 (Ref1)/activator protein-1 (AP-1) pathway. Mice underwent bile duct ligation (BDL) and were infused with AEA for 3 days postsurgery. Proliferation and apoptosis were evaluated in liver sections. Effects of in vitro AEA treatment on cholangiocyte proliferation and apoptosis were studied in purified cholangiocytes. The relative expression of cannabinoid receptors was also assessed in liver sections and cholangiocytes. mRNA expression of the cannabinoid receptors Cb1 and VR1 was decreased after BDL, whereas there was an upregulation of Cb2 mRNA. AEA decreased cholangiocyte growth and induced accumulation of reactive oxygen species, upregulation of TRX1, Ref1, c-Fos, and c-Jun expression, increased nuclear localization of TRX1, and increased AP-1 transcriptional activity. Specific knockdown of TRX1 or Ref1 expression ablated the AP-1 transcriptional activity and AEA-induced cell death but not expression of c-Fos and c-Jun. Knockdown of c-Fos and c-Jun expression also ablated AEA-induced apoptosis. We conclude that AEA suppresses cholangiocyte proliferation during cholestasis via a Cb2-dependent mechanism. Modulation of the endocannabinoid system may be important in the treatment of cholangiopathies.

endocannabinoids; biliary epithelia; cell proliferation; apoptosis; Fos; Jun


Address for reprint requests and other correspondence: S. DeMorrow, Division of Research and Education, Scott & White Hospital, Dept. of Internal Medicine, Texas A&M Health Science Center, Medical Research Bldg., 702 SW H. K. Dodgen Loop, Temple, TX 76504 (e-mail: demorrow{at}medicine.tamhsc.edu)




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