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To explore the mechanism of transdifferentiation, we examined whether inflammatory cytokines affected the phenotype of hepatocytes in a three\u2010dimensional culture system. Spheroidal aggregates of rat hepatocytes were embedded within a type I collagen gel matrix and cultured in the presence of various cytokines. In the control, hepatocytes gradually lost expression of albumin, tyrosine aminotransferase, and hepatocyte nuclear factor (HNF)\u20104\u03b1, while aberrantly expressed bile ductular markers, including cytokeratin 19 (CK 19) and spermatogenic immunoglobulin superfamily (SgIGSF). Among the cytokines examined, tumor necrosis factor (TNF)\u2010\u03b1 inhibited expression of albumin and HNF\u20104\u03b1, both at mRNA and protein levels. After culturing for 2 weeks with TNF\u2010\u03b1, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK 19\u2010 and SgIGSF\u2010positive small cuboidal cells. These cells responded to secretin with an increase in secretion and expressed functional bile duct markers. TNF\u2010\u03b1 also induced the phosphorylation of Jun N\u2010terminal kinase (JNK) and c\u2010Jun, and the morphogenesis was inhibited by SP600125, a specific JNK inhibitor. Furthermore, in chronic rat liver injury induced by CCl<jats:sub>4<\/jats:sub>, ductular reaction in the centrilobular area demonstrated strong nuclear staining of phosphorylated c\u2010Jun. Our results demonstrate that TNF\u2010\u03b1 promotes the ductular transdifferentiation of hepatocytes and suggest a role of TNF\u2010\u03b1 in the pathogenesis of ductular reaction. J. Cell. Biochem. 114: 831\u2013843, 2013. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jcb.24424","type":"journal-article","created":{"date-parts":[[2012,10,23]],"date-time":"2012-10-23T17:17:45Z","timestamp":1351012665000},"page":"831-843","source":"Crossref","is-referenced-by-count":23,"title":["Tumor necrosis factor\u2010\u03b1 promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro"],"prefix":"10.1002","volume":"114","author":[{"given":"Yuji","family":"Nishikawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Sone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuharu","family":"Nagahama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eriko","family":"Kumagai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Doi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasufumi","family":"Omori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuo","family":"Tokairin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yohei","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiro","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuhiko","family":"Enomoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,2,18]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2006.07.023"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-008-9067-1"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.132.6.1133"},{"key":"e_1_2_6_5_1","first-page":"G387","article-title":"Mechanisms of hepatic toxicity. 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