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 modula tion of cholangiocyte proliferation. Methods: ER-alpha and ER-beta weve ana lyzed by immunohistochemistry, reverse-transcription polymerase chain react ion, and Western blotting in normal and BDL rats. The effects of the ER ant agonists tamoxifen and ICI 182,780 on cholangiocyte proliferation were eval uated. 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 cholan giocytes in 3-week BDL than in normal rats; immunoreactivity for ER-beta sh owed 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 tamoxife n or ICI 182,780 of 3-week BDL vats inhibited cholangiocyte proliferation a nd induced overexpression of Fas antigen and apoptosis in cholangiocytes. I n vitro, 17 beta estradiol stimulated proliferation of cholangiocyte, an ef fect blocked to the same extent by tamoxifen or ICI 182,780. Conclusions: T his study suggests that estrogens and their receptors play a role in the mo dulation of cholangiocyte proliferation.