Estrogen Regulation of Cholangiocyte Proliferation
Recent data demonstrate that estrogens and their receptors play an important role in modulating cholangiocyte proliferation. Rat cholangiocytes, in fact, express estrogen receptors (ER)-α and -β subtypes, which are overexpressed in cholangiocytes proliferating after bile duct ligation (BDL) in the rat, in association with enlarged bile duct mass and with enhanced estradiol serum levels. Estrogen antagonists (tamoxifen, ICI 182, 780) impair cholangiocyte proliferation, during BDL, and activate Fas mediated apoptosis. In addition, ovariectomy depresses cholangiocyte proliferation during BDL an effect reversed by estrogen replacement treatment. Definitive evidences on the role of estrogens as modulators of cholangiocyte proliferation derive by studies in vitro showing how 17-beta-estradiol induces cholangiocyte proliferation. As far as the intracellular pathways are concerned, we demonstrate that estrogens induce proliferation by activating the Src/Shc/ERK pathway in cholangiocytes suggesting a possible synergistic effect with growth factors. In conclusion, our data indicate that estrogens are important modulators of cholangiocyte proliferation and this open new interesting perspectives for the physiopathology and treatment of cholangiopathies, a group of chronic cholestatic liver diseases preferentially affecting the female sex.