Tumor necrosis factor-α promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro
著者
西川, 祐司
(Nishikawa, Yuji)
Sone, Masayuki
Nagahama, Yasuharu
Kumagai, Eriko
Doi, Yuko
Omori, Yasufumi
Yoshioka, Toshiaki
Tokairin, Takuo
Yoshida, Masayuki
Yamamoto, Yohei
Ito, Akihiko
Sugiyama, Toshihiro
Enomoto, Katsuhiko
上位タイトル
Journal of cellular biochemistry
Vol.114,
No.4
(2013.
4)
,p.831-
843
識別番号
ISSN
0730-2312
DOI
10.1002/jcb.24424
その他
PMID：23097189
抄録
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.
