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Am J Physiol Gastrointest Liver Physiol 295: G124-G136, 2008. First published May 29, 2008; doi:10.1152/ajpgi.00536.2007
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LIVER AND BILIARY TRACT

Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms

Shannon Glaser,1,2 Sharon DeMorrow,1,2 Heather Francis,2 Yoshiyuki Ueno,5 Eugenio Gaudio,3 Shelley Vaculin,4 Julie Venter,1 Antonio Franchitto,3 Paolo Onori,9 Bradley Vaculin,1 Marco Marzioni,6 Candace Wise,1 Metaneeya Pilanthananond,1 Jennifer Savage,1 Lisa Pierce,8 Romina Mancinelli,1,3 and Gianfranco Alpini1,4,7

1Department of Medicine, 2Division of Research and Education, Scott & White Hospital and Texas A&M University System Health Science Center, College of Medicine, Temple, Texas; 3Department of Human Anatomy, University of Rome, La Sapienza, Rome, Italy; 4Division of Research, Central Texas Veterans Health Care System, Temple, Texas; 5Division of Gastroenterology, Tohoku University School of Medicine, Sendai, Japan; 6Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy; 7Department of Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; 8Department of Obstetrics and Gynecology, Scott & White Memorial Hospital and Texas A&M Health Science Center, College of Medicine, Temple, Texas; and 9Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy

Submitted 16 November 2007 ; accepted in final form 22 May 2008

During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine mechanisms. We examined whether the neuroendocrine hormone progesterone is produced by and targeted to cholangiocytes, thereby regulating biliary proliferation during cholestasis. Nuclear (PR-A and PR-B) and membrane (PRGMC1, PRGMC2, and mPR{alpha}) progesterone receptor expression was evaluated in liver sections and cholangiocytes from normal and bile duct ligation (BDL) rats, and NRC cells (normal rat cholangiocyte line). In vivo, normal rats were chronically treated with progesterone for 1 wk, or immediately after BDL, rats were treated with a neutralizing progesterone antibody for 1 wk. Cholangiocyte growth was measured by evaluating the number of bile ducts in liver sections. The expression of the progesterone synthesis pathway was evaluated in liver sections, cholangiocytes and NRC. Progesterone secretion was evaluated in supernatants from normal and BDL cholangiocytes and NRC. In vitro, NRC were stimulated with progesterone and cholangiocyte supernatants in the presence or absence of antiprogesterone antibody. Aminoglutethimide was used to block progesterone synthesis. Cholangiocytes and NRC express the PR-B nuclear receptor and PRGMC1, PRGMC2, and mPR{alpha}. In vivo, progesterone increased the number of bile ducts of normal rats, whereas antiprogesterone antibody inhibited cholangiocyte growth stimulated by BDL. Normal and BDL cholangiocytes expressed the biosynthetic pathway for and secrete progesterone. In vitro, 1) progesterone increased NRC proliferation; 2) cholangiocyte supernatants increased NRC proliferation, which was partially inhibited by preincubation with antiprogesterone; and 3) inhibition of progesterone steroidogenesis prevented NRC proliferation. In conclusion, progesterone may be an important autocrine/paracrine regulator of cholangiocyte proliferation.

bile ducts; gastrointestinal hormones; intrahepatic biliary epithelium


Addresses for reprint requests and other correspondence: S. Glaser, Scott & White Hospital, Texas A&M Health Science Center, 702 SW H. K. Dodgen Loop, Temple, TX 76504 (e-mail: sglaser{at}tamu.edu) and G. Alpini, Medicine and Systems Biology and Translation Medicine, Central Texas Veterans Health Care System, Texas A&M Health Science Center, College of Medicine, Medical Research Bldg., 702 SW H. K. Dodgen Loop, Temple, TX 76504 (e-mail: galpini{at}tamu.edu or galpini{at}medicine.tamhsc.edu)




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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
R. Mancinelli, P. Onori, E. Gaudio, S. DeMorrow, A. Franchitto, H. Francis, S. Glaser, G. Carpino, J. Venter, D. Alvaro, et al.
Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1
Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G11 - G26.
[Abstract] [Full Text] [PDF]


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