2007 Fiscal Year Final Research Report Summary
Roles of TNF-α in ductular metaplasia of hepatocytes
| Project/Area Number |
18590362
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Akita University |
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Principal Investigator |
NISHIKAWA Yuji Akita University, School of Medicine, Associate Professor (90208166)
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| Co-Investigator(Kenkyū-buntansha) |
OMORI Yasufumi Akita University, School of Medicine, Lecturer (90323138)
YOSHIOKA Toshiaki Akita University, School of Medicine, Assistant Professor (80302264)
ENOMOTO Katsuhiko Akita University, School of Medicine, Professor (20151988)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Hepatocytes / Bile duct cells / Ductular Metaplasia / TNF-α / JNK-c-Jun pathway / Collagen gels / Three-dimensional culture |
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| Research Abstract |
There have been several lines of evidence showing that mature hepatocytes can transdifferentiate into bile ductular cells both in vivo and in vitro, although the mechanism is unclear. We examined whether cytokines produced by Kupffer cells affected the phenotype of hepatocytes in a three-dimensional culture system. Here, we report that tumor necrosis factor α (TNF-α) is a cytokine which strongly induces bile ductular differentiation of hepatocytes. Spheroidal aggregates of rat hepatocytes were embedded within a type I collagen gel matrix and cultured in the presence of various cytokines. Among those tested, TNF-α inhibited albumin expression, while enhanced the expression of cytokeratin 19 (CK19) and spermatogenic immunoglobulin superfamily (SgIGSF). After 2 to 3 weeks in the presence of TNF-α, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK19-positive cells. These cells responded to secretin with an increased secretion and expressed functional bile duct markers. TNF-α induced phosphorylation of Jun N-terminal kinase (JNK) and c-Jun, and the morphogenesis was inhibited by a JNK inhibitor. When these ductular cells were retrieved from gels by collagenase digestion and cultured on Matrigel, they gradually recovered hepatocytic phenotype. Our results suggest that TNF-α promote ductular differentiation of hepatocytes via the JNK-c-Jun pathway and that the transdifferentiation is at least partly reversible.
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[Journal Article] Osteopontin expression in the liver with severe perisinusoidal fibrosis : Autopsy case of Down syndrome with transient myeloproliferative disorder2008
Author(s)
Tokairin T, Nishikawa Y, Watanabe H, Doi Y, Omori Y, Yoshioka T, Yamamoto Y, Yoshida M, Nishimura T, Li Q, Arai H, Ishida A, Takada G, Enomoto K.
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Journal Title
Pathol. Int 58
Pages: 64-68
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Epithelial-to-mesenchymal transition(EMT)induced by P120BP-1,a newly-identified p120 catenin-binding protein.2006
Author(s)
Omori, Y, Takahashi, Y, Ishizaki, Y, Nishikawa, Y, et. al.
Organizer
20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
Place of Presentation
Kyoto, Janpan
Year and Date
20060700
Description
「研究成果報告書概要(和文)」より
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