Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats

Background & Aims: We investigated the expression of estrogen receptor (ER) \u3b1 and \u3b2 subtypes in cholangiocytes of normal and bile duct-ligated (BDL) rats and evaluated the role and mechanisms of estrogens in the modulation of cholangiocyte proliferation. Methods: ER-\u3b1 and ER-\u3b2 were analyzed by immunohistochemistry, reverse-transcription polymerase chain reaction, and Western blotting in normal and BDL rats. The effects of the ER antagonists tamoxifen and ICI 182, 780 on cholangiocyte proliferation were evaluated. Results: Cholangiocytes expressed both ER-\u3b1 and ER-\u3b2 subtypes, whereas hepatocytes expressed only ER-\u3b1. In association with a marked cholangiocyte proliferation and with enhanced estradiol serum levels, the immunoreactivity for ER-\u3b1 involved a 3-fold higher percentage of cholangiocytes in 3-week BDL than in normal rats; immunore-activity for ER-\u3b2 showed a 30-fold increase. Western blot analysis showed that during BDL, the total amount of ER-\u3b2 in cholangiocytes was markedly increased (5-fold), whereas that of ER-\u3b1 decreased slightly (-25%). Treatment with tamoxifen or ICI 182, 780 of 3-week BDL rats inhibited cholangiocyte proliferation and induced over-expression of Fas antigen and apoptosis in cholangiocytes. In vitro, 17\u3b2 estradiol stimulated proliferation of cholangiocyte, an effect blocked to the same extent by tamoxifen or ICI 182, 780. Conclusions: This study suggests that estrogens and their receptors play a role in the modulation of cholangiocyte proliferation