Department of Pathology, Division of Transplantation, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Hepatology. 2010 Mar;51(3):869-80. doi: 10.1002/hep.23386.
Females are more susceptible than males to several biliary tract diseases. Interleukin-6 (IL-6) is critical to triggering autoimmune reactions and contributes substantially to biliary epithelial cell (BEC) barrier function and wound repair, and estrogen differentially regulates IL-6 expression in various cell types. We hypothesized that estrogen might stimulate BEC IL-6 production. Exposure to physiologic levels of estradiol, in vitro, increased female mouse BEC (mBEC) IL-6 messenger RNA (mRNA) and protein expression, but either inhibited or had no effect on male mBECs. Female mBECs expressed higher concentrations of estrogen receptor-alpha (ERalpha) mRNA and protein and were also more dependent on estradiol for survival, in vitro. In vivo, elevated estrogen during estrous cycling in mice, and estrogen treatment of mice harboring an ERalpha(+) human cholangiocarcinoma resulted in increased BEC IL-6 mRNA and tumor viability, respectively. Both responses could be blocked by an ERalpha antagonist. Human cholangiocarcinoma cell lines differentially expressing ERalpha were treated with specific ERalpha and ERbeta agonists/antagonists to further test the relationship between estrogen stimulation, ERalpha expression, and IL-6 production. Results show that ERalpha, and not the underlying BEC sex, was responsible for estrogen-induced IL-6 production. Estrogen-induced proliferation of ERalpha-expressing cholangiocarcinoma was blocked by anti-IL-6 antibodies, indicating that at least some of the estrogen-trophic effects are mediated via IL-6. Finally, an association between ERalpha, IL-6, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) signaling was shown in female-predominant polycystic livers using immunohistochemical analyses, including multiplex quantum dot labeling.
Estrogens stimulate IL-6 production in non-neoplastic female BECs and in neoplastic BECs expressing ERalpha. An association between these signaling pathways was demonstrated for female-predominant polycystic livers and might also influence autoimmune hepatitis, primary biliary cirrhosis, and cholangiocarcinogenesis.
女性比男性更容易患上几种胆道疾病。白细胞介素 6（IL-6）对引发自身免疫反应至关重要，并对胆管上皮细胞（BEC）的屏障功能和伤口修复有很大贡献，雌激素对不同细胞类型的 IL-6 表达有差异调节作用。我们假设雌激素可能会刺激 BEC 的 IL-6 产生。在体外，暴露于生理水平的雌二醇会增加雌性小鼠 BEC（mBEC）的 IL-6 信使 RNA（mRNA）和蛋白表达，但对雄性 mBEC 要么抑制，要么没有影响。雌性 mBEC 表达更高浓度的雌激素受体-α（ERα）mRNA 和蛋白，并且在体外也更依赖雌二醇生存。在体内，在小鼠发情周期中雌激素水平升高，以及用雌激素治疗携带 ERα（+）人胆管癌的小鼠，分别导致 BEC IL-6 mRNA 和肿瘤活力增加。这两种反应都可以被 ERα 拮抗剂阻断。用特异性 ERα 和 ERβ 激动剂/拮抗剂处理表达 ERα 的人胆管癌细胞系，以进一步测试雌激素刺激、ERα 表达和 IL-6 产生之间的关系。结果表明，是 ERα，而不是潜在的 BEC 性别，负责雌激素诱导的 IL-6 产生。抗 IL-6 抗体阻断了 ERα 表达的胆管癌细胞的增殖，表明至少部分雌激素营养作用是通过 IL-6 介导的。最后，在使用免疫组织化学分析，包括多重量子点标记，对女性为主的多囊肝进行了 ERα、IL-6 和磷酸化信号转导和转录激活因子 3（pSTAT3）信号之间的关联。
雌激素刺激非肿瘤性雌性 BEC 和表达 ERα 的肿瘤性 BEC 中 IL-6 的产生。在女性为主的多囊肝中证明了这些信号通路之间的关联，也可能影响自身免疫性肝炎、原发性胆汁性肝硬化和胆管癌发生。
