Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1

• DOI: 10.1152/ajpgi.00025.2009
• Publication Date: 2009-04-24T00:35:00Z
• Authors: Romina Mancinelli; Paolo Onori; Eugenio Gaudio; Sharon DeMorrow; Antonio Franchitto; Heather Francis; Shannon Glaser; Guido Carpino; Julie Venter; Domenico Alvaro; Shelley Kopriva; Mellanie White; Ashley Kossie; Jennifer Savage; Gianfranco Alpini
• Keywords: Male; 0303 health sciences; Cholestasis; Apoptosis; Infusion Pumps, Implantable; Inositol 1,4,5-Trisphosphate; Antibodies; Autocrine Communication; Disease Models, Animal; 03 medical and health sciences; Hormone Antagonists; Liver; Culture Media, Conditioned; Cyclic AMP; Hepatocytes; Animals; Female; Bile Ducts; Follicle Stimulating Hormone; Ligation; Cells, Cultured; biliary epithelium; map kinase; sex hormones; neuroendocrine hormones; Cell Proliferation

Sex hormones regulate cholangiocyte hyperplasia in bile duct-ligated (BDL) rats. We studied whether follicle-stimulating hormone (FSH) regulates cholangiocyte proliferation. FSH receptor (FSHR) and FSH expression was evaluated in liver sections, purified cholangiocytes, and cholangiocyte cultures (NRICC). In vivo, normal female and male rats were treated with FSH or immediately after BDL with antide (a gonadotropin-releasing hormone antagonist blocking FSH secretion) or a neutralizing FSH antibody for 1 wk. We evaluated 1) cholangiocyte proliferation in sections and cholangiocytes and 2) changes in secretin-stimulated cAMP (functional index of cholangiocyte growth) levels, and ERK1/2 and Elk-1 phosphorylation. NRICC were stimulated with FSH before evaluation of proliferation, cAMP/IP3levels, and ERK1/2 and Elk-1 phosphorylation. To determine whether FSH regulates cholangiocyte proliferation by an autocrine mechanism, we evaluated the effects of 1) cholangiocyte supernatant (containing FSH) on NRICC proliferation and 2) FSH silencing in NRICC before measuring proliferation and ERK1/2 and Elk-1 phosphorylation. Cholangiocytes and NRICC express FSHR and FSH and secrete FSH. In vivo administration of FSH to normal rats increased, whereas administration of antide and anti-FSH antibody to BDL rats decreased 1) ductal mass and 2) secretin-stimulated cAMP levels, proliferation, and ERK1/2 and Elk-1 phosphorylation in cholangiocytes compared with controls. In NRICC, FSH increased cholangiocyte proliferation, cAMP levels, and ERK1/2 and Elk-1 phosphorylation. The supernatant of cholangiocytes increased NRICC proliferation, inhibited by preincubation with anti-FSH antibody. Silencing of FSH gene decreases cholangiocyte proliferation and ERK1/2 and Elk-1 phosphorylation. Modulation of cholangiocyte FSH expression may be important for the management of cholangiopathies.