37 We confirmed that estrogens inhibit macrophage IL-6 production in both sexes, but in BECs, estrogen-induced IL-6 expression is sex dependent. This might partially explain why the dramatic sex disparity for hepatocellular carcinoma does not exist for cholangiocarcinoma,38, 39 because STAT3 plays a critical role in tumor initiation and promotion.40 In fact, hepatocellular carcinoma is the most common primary liver neoplasm in males, whereas cholangiocarcinoma is the most common primary liver neoplasm in females.39 In addition, a majority of cholangiocarcinomas express ERα, regardless of sex, and preferential expression

of ERα is associated with estradiol-induced cholangiocarcinoma Protein Tyrosine Kinase inhibitor growth.41 Our in vivo studies show that estrogen is involved in cell survival by inhibiting apoptosis and necrosis, which may have therapeutic implications for bile duct injury. In addition, fulvestrant significantly increased apoptosis and inhibited tumor growth, which might be a useful tool for cholangiocarcinomas and PCL disease. Finally, this study provides some insights into BEC sex differences that could influence non-neoplastic disease pathogenesis. For example, liver cyst growth might be accelerated in females17 because of the estrogen-induced mitogenic influence of BEC IL-6 expression.29 We showed a temporal-spatial and

statistical association among ERα, IL-6, and pSTAT3 signaling Akt inhibitor in cystic epithelium, consistent with previous studies showing increased IL-6 concentrations within cyst fluid.21 We also analyzed a variety of other factors associated with PCL. A significant relationship was found only between ERα, pSTAT3, and menopausal status and the strongest relationship with pSTAT3 levels was with IL-6. In women, liver cysts

frequently emerge at puberty and continue to grow throughout the child-bearing years.33 This data suggests that a patient’s menopausal status influences cyst Carnitine palmitoyltransferase II enlargement via ERα/IL-6/pSTAT3 signaling, but we cannot exclude the contribution of other previously studied factors to cyst growth. We also showed that female mBEC IL-6 mRNA and bile IL-6 protein expression vary throughout the estrous cycle. IL-6 is required to sustain TH17-type T lymphocytes, but inhibits regulatory T cell production,22, 42 and is required for plasma cell differentiation.43 Therefore, it is not unreasonable to suggest that the differential hepatic IL-6 microenvironment that occurs as a consequence of BEC estrogen responsiveness might contribute to the pathogenesis of diseases such as PBC and autoimmune hepatitis, which are associated with TH17 autoimmunity44 and localized plasma cell differentiation. Additional Supporting Information may be found in the online version of this article. “
“The impact of renal dysfunction has not been well evaluated among cirrhotic patients having bacterial infections other than spontaneous bacterial peritonitis (SBP).