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Journal of Cellular Biochemistry

Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro

Authors

  • Yuji Nishikawa,

    Corresponding author
    1. Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Higashi 2-1-1-1 Midorigaoka, Asahikawa, Hokkaido 078-8510, Japan
    • Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Higashi 2-1-1-1 Midorigaoka, Asahikawa, Hokkaido 078-8510, Japan.
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  • Masayuki Sone,

    1. Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., 1-11-1 Karasaki, Otsu, Shiga 520-0106, Japan
    2. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Yasuharu Nagahama,

    1. Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Higashi 2-1-1-1 Midorigaoka, Asahikawa, Hokkaido 078-8510, Japan
    2. Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., 1-11-1 Karasaki, Otsu, Shiga 520-0106, Japan
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  • Eriko Kumagai,

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Yuko Doi,

    1. Central Research Laboratory, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Yasufumi Omori,

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Toshiaki Yoshioka,

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Takuo Tokairin,

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Masayuki Yoshida,

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Yohei Yamamoto,

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Akihiko Ito,

    1. Department of Pathology, Kinki University Faculty of Medicine, Ohno Higashi 377-2, Sayama, Osaka 589-8511, Japan
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  • Toshihiro Sugiyama,

    1. Department of Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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  • Katsuhiko Enomoto

    1. Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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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 CCl4, 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. J. Cell. Biochem. 114: 831–843, 2013. © 2012 Wiley Periodicals, Inc.

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