Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers

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• 作者：Minoru Nakamura (1) (2)
  Kenji Funami (3)
  Atsumasa Komori (1)
  Terufumi Yokoyama (1)
  Yoshihiro Aiba (1)
  Aiko Araki (1)
  Yasushi Takii (1)
  Masahiro Ito (1)
  Mutsumi Matsuyama (1)
  Makiko Koyabu (1)
  Kiyoshi Migita (1)
  Ken Taniguchi (1)
  Hikaru Fujioka (1)
  Hiroshi Yatsuhashi (1)
  Misako Matsumoto (3)
  Hiromi Ishibashi (1)
  Tsukasa Seya (3)
  
• 关键词：Primary biliary cirrhosis (PBC) ; Human intrahepatic biliary epithelial cells (HIBECs) ; Interferon beta (IFN ; β) ; Toll ; like receptor 3 (TLR3) Toll ; IL ; 1R homology domain ; containing adaptor molecule 1 (TICAM ; 1) ; Mitochondrial antiviral signaling protein (MAVS) ; Retinoic acid inducible gene I (RIG ; I) ; Melanoma differentiation ; associated gene 5 (MDA5)
• 刊名：Hepatology International
• 出版年：2008
• 出版时间：June 2008
• 年：2008
• 卷：2
• 期：2
• 页码：222-230
• 全文大小：440KB
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• 作者单位：Minoru Nakamura (1) (2)
  Kenji Funami (3)
  Atsumasa Komori (1)
  Terufumi Yokoyama (1)
  Yoshihiro Aiba (1)
  Aiko Araki (1)
  Yasushi Takii (1)
  Masahiro Ito (1)
  Mutsumi Matsuyama (1)
  Makiko Koyabu (1)
  Kiyoshi Migita (1)
  Ken Taniguchi (1)
  Hikaru Fujioka (1)
  Hiroshi Yatsuhashi (1)
  Misako Matsumoto (3)
  Hiromi Ishibashi (1)
  Tsukasa Seya (3)
  
  1. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan
  2. Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan
  3. Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  

文摘

Background Toll-like receptors (TLRs) may play active roles in both innate and adaptive immune responses in human intrahepatic biliary epithelial cells (HIBECs). The role of TLR3 expressed by HIBECs, however, remains unclear. Methods We determined the in vivo expression of TLRs in biopsy specimens derived from diseased livers immunohistochemically using a panel of monoclonal antibodies against human TLRs. We then examined the response of cultured HIBECs to a TLR3 ligand, polyinosinic–polycytidylic acid (polyI:C). Using siRNAs specific for Toll-IL-1R homology domain-containing adaptor molecule 1 (TICAM-1) and mitochondrial antiviral signaling protein (MAVS), we studied signaling pathways inducing IFN-β expression. Results The expression of TLR3 was markedly increased in biliary epithelial cells at sites of ductular reaction in diseased livers, including primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and chronic viral hepatitis (CH) as compared to nondiseased livers. Although cultured HIBECs constitutively expressed TLR3 at both the protein and mRNA levels in vitro, the addition of polyI:C to culture media induced only minimal increases in IFN-β mRNA. In contrast, transfection of HIBECs with polyI:C induced a marked increase in mRNAs encoding a variety of chemokines/cytokines, including IFN-β, IL-6, and TNF-α. The induction of IFN-β mRNA was efficiently inhibited by an siRNA against MAVS but not against TICAM-1, indicating that the main signaling pathway for IFN-β induction following polyI:C transfection is via retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) in HIBECs. Conclusions TLR3 expression by biliary epithelial cells increased at sites of ductular reaction in diseased livers; further study will be necessary to characterize it’s in vivo physiological role.