The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis.
OBJECTIVE
We evaluated the role and mechanisms by which the GH/IGF1 axis modulates cholangiocyte proliferation.


METHODS
GH-receptors (GH-R), IGF1, IGFBP3 (binding protein 3), IGF1-R and receptor substrates (IRS) were evaluated in cholangiocytes of normal or bile duct-ligated (BDL) rat livers. The effects of GH and IGF1 on proliferation of normal quiescent cholangiocytes and the transduction pathways involved were investigated.


RESULTS
IGF1, GH-R, IGF1-R, IRS-1/2 were expressed in normal cholangiocytes and overexpressed in cholangiocytes proliferating after BDL which also secrete IGF1 in a higher amount than normal cells. IGFBP3, which may counter-regulate IGF1 effects, was decreased in BDL cholangiocytes. IGF1 promoted cholangiocyte proliferation in association with overexpression of p-IGF1R, IRS1, IRS-2, p-ERK1/2 and p-AKT. GH induced IGF1 expression and release in isolated cholangiocytes, and reproduced the effects of IGF1 but GH effects were abolished by IGF1-R blocking antibody, suggesting IGF1 as a mediator of GH. Finally, IGF1 and 17beta-estradiol reciprocally potentiated their proliferative effects on cholangiocytes, and by interacting at both receptor and post-receptor levels.


CONCLUSIONS
Cholangiocytes respond to GH with production and release of IGF1 that modulates cell proliferation by transduction pathways involving IGF1-R, IRS1/2 and both ERK and PI3-kinase pathways. The biliary epithelium is a target of GH/IGF1 liver axis.
Alvaro
Domenico
D
Division of Gastroenterology, University of Rome, La Sapienza, Rome, Italy. domenico.alvaro@uniroma1.it
Metalli
Veronica Drudi
VD
Alpini
Gianfranco
G
Onori
Paolo
P
Franchitto
Antonio
A
Barbaro
Barbara
B
Glaser
Shannon S
SS
Francis
Heather
H
Cantafora
Alfredo
A
Blotta
Ida
I
Attili
Adolfo Francesco
AF
Gaudio
Eugenio
E
D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000033:anatomy & histology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases