In addition, the selective ERα agonist PPT stimulates BEC IL-6 production, whereas the ERα antagonist fulvestrant16 and the

selective ERβ agonist DPN inhibit the estrogen-induced BEC IL-6 production. Conversely, increasing ERα protein in non-neoplastic male BECs with chronic estrogen exposures enables estrogen-responsiveness HDAC inhibitor in normally nonresponsive cells. Persistent expression of ERα in female BECs, in the absence of an exogenous estrogen source, also renders them more vulnerable to estrogen deficiency in vitro. In vivo, estrogen enhanced tumor viability of ERα-positive cholangiocarcinoma cells by reducing apoptosis and necrosis and increasing IL-6 expression. Previous studies have shown similar results for non-neoplastic BECs.17 Regardless, we also showed that the trophic effect of estrogen on isolated BECs is mediated, at least in part, by stimulating IL-6 production. Alvaro et al. found a role for IGF-1 in estrogen-mediated BEC proliferation.31 The current study also

showed IGF-1 and pIGF-1R expression in cystic BECs, which is not usually seen in normal BECs, but there was not a significant correlation with pSTAT3 signaling as seen with IL-6. Other factors, such as VEGF, Nutlin-3 purchase Flk-1, EGFR, and HER2/erbB-2 were also investigated and some showed a trend, but the association was statistically significant only for pSTAT3 and IL-6. This is consistent

with the observation that, in women, liver cysts frequently emerge at puberty and increase throughout the child-bearing years,33 suggesting that estrogen/IL-6/pSTAT3 signaling stimulates cyst growth. Both in vitro and in vivo data showed that estrogen treatment reduced cell death and increased IL-6 expression in ERα-expressing BECs (Fig. 3). Because IL-6 is critical to BEC barrier function and wound healing,9 similar to the skin7 and gastrointestinal8 tracts, the estrogen deficiency of menopause and female-to-male liver transplants likely diminishes two critical trophic factors for BECs: direct estrogen stimulation17 and estrogen-induced IL-6 expression.9 Male BECs are able to adjust to an estrogen-rich environment, whereas female BECs still express higher Methocarbamol ERα protein levels than male BECs in an estrogen-poor environment This result is consistent with the observation that ERα is normally expressed at low levels in some normal male human tissues.34 In addition, chronic estrogen therapy up-regulates ERα protein expression in tissues of human male-to-female transsexuals.35 This might help to explain the significantly lower survival of female-to-male liver allografts and why they experience a higher rate of biliary tract complications36 compared to other donor-recipient sex combinations.