Gender Differences in Estrogen Regulation of Intrahepatic Biliary Epithelial Cell IL‐6 Expression

Females are significantly more susceptible to primary biliary cirrhosis and debilitating consequences of adult polycystic liver disease than males. Also, biliary strictures contribute to poor outcome of female‐to‐male liver transplant compared to other donor‐recipient sex combinations. Since IL‐6 is critically important in biliary epithelial barrier function and wound repair and estrogens regulate IL‐6 expression, we tested the hypothesis that estrogens differentially regulate biliary epithelial cell (BEC) IL‐6 production in males and females. Results show that estradiol treatment either inhibited or had no effect on male mBEC IL‐6 expression but increased female IL‐6 expression. Male mBEC expressed less estrogen receptor‐alpha (ERα) protein than female mBEC but had similar levels of estrogen receptor‐beta (ER β). Female mBEC were also more dependent on estradiol for robust survival. Male mBEC, however, in an estrogen‐rich environment, upregulated ERα and then became estrogen‐responsive. In vivo studies show that biliary epithelia from female mice in estrus expressed IL‐6, but anestrus female mice did not. Experiments in two male human cholangiocarcinoma cell lines showed that signaling through ERα, and not the underlying sex, was responsible for the differential regulation of IL‐6 by estrogen. In conclusion, female BEC are estrogen responsive and dependent because of higher levels of ERα. Male BEC can adapt to an estrogen‐rich environment by upregulating ERα. Since estrogens can influence BEC barrier functions and wound healing both directly and indirectly via IL‐6 signalling, the differential regulation of BEC IL‐6 in males and females likely contribute significantly to sex differences seen in biliary diseases and cross‐sex liver transplants.