Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1.
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/IP(3) levels, 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.
Mancinelli
Romina
R
Department of Medicine, Division Gastroenterology, Texas A&M Health Science Center, College of Medicine, Texas, USA.
Onori
Paolo
P
Gaudio
Eugenio
E
DeMorrow
Sharon
S
Franchitto
Antonio
A
Francis
Heather
H
Glaser
Shannon
S
Carpino
Guido
G
Venter
Julie
J
Alvaro
Domenico
D
Kopriva
Shelley
S
White
Mellanie
M
Kossie
Ashley
A
Savage
Jennifer
J
Alpini
Gianfranco
G
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis; D019898:Autocrine Communication / Q000187:drug effects; D001652:Bile Ducts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002779:Cholestasis / Q000201:enzymology* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D006727:Hormone Antagonists / Q000008:administration & dosage; D015918:Infusion Pumps, Implantable; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D011962:Receptors, FSH / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
D000906:Antibodies; D017077:Culture Media, Conditioned; C494114:Elk1 protein, rat; D006727:Hormone Antagonists; D009842:Oligopeptides; D011962:Receptors, FSH; D050807:ets-Domain Protein Elk-1; D015544:Inositol 1,4,5-Trisphosphate; D005640:Follicle Stimulating Hormone; C057022:iturelix; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3