title: Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro.
abstract: We previously showed that mature hepatocytes could transdifferentiate into bile ductular cells when placed in a collagen-rich microenvironment. To explore the mechanism of transdifferentiation, we examined whether inflammatory cytokines affected the phenotype of hepatocytes in a three-dimensional 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)-4α, while aberrantly expressed bile ductular markers, including cytokeratin 19 (CK 19) and spermatogenic immunoglobulin superfamily (SgIGSF). Among the cytokines examined, tumor necrosis factor (TNF)-α inhibited expression of albumin and HNF-4α, both at mRNA and protein levels. After culturing for 2 weeks with TNF-α, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK 19- and SgIGSF-positive small cuboidal cells. These cells responded to secretin with an increase in secretion and expressed functional bile duct markers. TNF-α also induced the phosphorylation of Jun N-terminal kinase (JNK) and c-Jun, and the morphogenesis was inhibited by SP600125, a specific JNK inhibitor. Furthermore, in chronic rat liver injury induced by CCl(4) , ductular reaction in the centrilobular area demonstrated strong nuclear staining of phosphorylated c-Jun. Our results demonstrate that TNF-α promotes the ductular transdifferentiation of hepatocytes and suggest a role of TNF-α in the pathogenesis of ductular reaction.
authors.affiliation: Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Higashi 2-1-1-1 Midorigaoka, Asahikawa, Hokkaido 078-8510, Japan. nishikwa@asahikawa-med.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sone
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nagahama
authors.forename: Eriko
authors.initials: E
authors.lastname: Kumagai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Doi
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Omori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Takuo
authors.initials: T
authors.lastname: Tokairin
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Enomoto
mesh_terms: D000418:Albumins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001652:Bile Ducts / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000009:adverse effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D048430:Cell Shape / Q000187:drug effects; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D053539:Keratin-19 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D009024:Morphogenesis / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D012633:Secretin / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000418:Albumins; D000873:Anthracenes; C465040:Cadm1 protein, rat; D015815:Cell Adhesion Molecules; D024042:Collagen Type I; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D007136:Immunoglobulins; D053539:Keratin-19; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D012633:Secretin; C432165:pyrazolanthrone; D002251:Carbon Tetrachloride