{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:00:32Z","timestamp":1790251232887,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2010,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>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,<\/jats:bold>\n                      <jats:bold>in vitro<\/jats:bold>\n                      <jats:bold>, 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 (ER\u03b1) mRNA and protein and were also more dependent on estradiol for survival,<\/jats:bold>\n                      <jats:bold>in vitro<\/jats:bold>\n                      <jats:bold>.<\/jats:bold>\n                      <jats:bold>In vivo<\/jats:bold>\n                      <jats:bold>, elevated estrogen during estrous cycling in mice, and estrogen treatment of mice harboring an ER\u03b1+ human cholangiocarcinoma resulted in increased BEC IL-6 mRNA and tumor viability, respectively. Both responses could be blocked by an ER\u03b1 antagonist. Human cholangiocarcinoma cell lines differentially expressing ER\u03b1 were treated with specific ER\u03b1 and ER\u03b2 agonists\/antagonists to further test the relationship between estrogen stimulation, ER\u03b1 expression, and IL-6 production. Results show that ER\u03b1, and not the underlying BEC sex, was responsible for estrogen-induced IL-6 production. Estrogen-induced proliferation of ER\u03b1-expressing cholangiocarcinoma was blocked by anti\u2013IL-6 antibodies, indicating that at least some of the estrogen-trophic effects are mediated via IL-6. Finally, an association between ER\u03b1, 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.<\/jats:bold>\n                      <jats:bold>Conclusion:<\/jats:bold>\n                      <jats:bold>Estrogens stimulate IL-6 production in non-neoplastic female BECs and in neoplastic BECs expressing ER\u03b1. An association between these signaling pathways was demonstrated for female-predominant polycystic livers and might also influence autoimmune hepatitis, primary biliary cirrhosis, and cholangiocarcinogenesis. (Hepatology 2010.)<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.23386","type":"journal-article","created":{"date-parts":[[2009,10,19]],"date-time":"2009-10-19T14:15:49Z","timestamp":1255961749000},"page":"869-880","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":45,"title":["Estrogen Stimulates Female Biliary Epithelial Cell Interleukin-6 Expression in Mice and Humans"],"prefix":"10.1097","volume":"51","author":[{"given":"Kumiko","family":"Isse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Specht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Lunz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-I","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Mizuguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Demetris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-18-20241201","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1096\/fj.00-0073com","article-title":"Impaired cutaneous wound healing in interleukin6deficient and immunosuppressed mice.","volume":"14","author":"Gallucci","year":"2000","journal-title":"FASEB J"},{"key":"R2-18-20241201","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1677\/joe.0.1710065","article-title":"Immunolocalization of estrogen receptor alpha and beta in gastric epithelium and enteric neurons.","volume":"171","author":"CampbellThompson","year":"2001","journal-title":"J Endocrinol"},{"key":"R3-18-20241201","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1006\/frne.1999.0190","article-title":"Estrogen is more than just a sex hormone: novel sites for estrogen action in the hippocampus and cerebral cortex.","volume":"21","author":"Shughrue","year":"2000","journal-title":"Front Neuroendocrinol"},{"key":"R4-18-20241201","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.jhep.2004.08.022","article-title":"Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis.","volume":"41","author":"Alvaro","year":"2004","journal-title":"J Hepatol"},{"key":"R6-18-20241201","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0531-5565(01)00197-8","article-title":"The 174 CG locus affects in vitroin vivo IL6 production during aging.","volume":"37","author":"Olivieri","year":"2002","journal-title":"Exp Gerontol"},{"key":"R7-18-20241201","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1189\/jlb.0802397","article-title":"Essential involvement of IL6 in the skin woundhealing process as evidenced by delayed wound healing in IL6deficient mice.","volume":"73","author":"Lin","year":"2003","journal-title":"J Leukoc Biol"},{"key":"R8-18-20241201","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/nm763","article-title":"Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STATmediated trefoil gene activation in gp130 mutant mice.","volume":"8","author":"Tebbutt","year":"2002","journal-title":"Nat Med"},{"key":"R9-18-20241201","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.3748\/wjg.v12.i22.3512","article-title":"3rd, Specht S, Nozaki I. 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