Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats

Background & Aims: We investigated the expression of estrogen receptor (ER) alpha and beta subtypes in cholangiocytes of normal and bile duct-ligated (BDL) vats and evaluated the vole and mechanisms of estrogens in the modulation of cholangiocyte proliferation. Methods: ER-alpha and ER-beta weve 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-alpha and ER-beta subtypes, whereas hepatocytes expressed only ER-alpha. In association with a marked cholangiocyte proliferation and with enhanced estradiol serum levels, the immunoreactivity for ER-alpha involved a 3-fold higher percentage of cholangiocytes in 3-week BDL than in normal rats; immunoreactivity for ER-beta showed a 30-fold increase. Western blot analysis showed that during BDL, the total amount of ER-beta in cholangiocytes was markedly increased (5-fold), whereas that of ER-alpha decreased slightly (-25%). Treatment with tamoxifen or ICI 182,780 of 3-week BDL vats inhibited cholangiocyte proliferation and induced overexpression of Fas antigen and apoptosis in cholangiocytes. In vitro, 17 beta 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.