Hepatology International

, Volume 2, Issue 2, pp 222–230 | Cite as

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

  • Minoru NakamuraEmail author
  • Kenji Funami
  • Atsumasa Komori
  • Terufumi Yokoyama
  • Yoshihiro Aiba
  • Aiko Araki
  • Yasushi Takii
  • Masahiro Ito
  • Mutsumi Matsuyama
  • Makiko Koyabu
  • Kiyoshi Migita
  • Ken Taniguchi
  • Hikaru Fujioka
  • Hiroshi Yatsuhashi
  • Misako Matsumoto
  • Hiromi Ishibashi
  • Tsukasa Seya
Original Article


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.


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) 



Biliary epithelial cell




Double stranded RNA


Endoplasmic reticulum


Enzyme-linked immunosorbent assay


Glyceraldehydes-3-phosphate dehydrogenase


Human intrahepatic biliary epithelial cell


Horseradish peroxidase






Interferon regulatory factor


Mitochondrial anti-viral signaling protein


Melanoma differentiation associated gene-5


Myeloid differentiation factor 88


Primary biliary cirrhosis


Peripheral blood mononuclear cells


Polyinosinic–polycytidylic acid


Pattern-recognition receptor


Retinoic acid-inducible gene I


Reverse transcription-polymerase chain reaction


Small interfering RNA


Toll-like receptor


Tumor necrosis factor


Toll-IL-1R homology domain containing adaptor molecule 1



This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.


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Copyright information

© Asian Pacific Association for the Study of the Liver 2008

Authors and Affiliations

  • Minoru Nakamura
    • 1
    • 2
    Email author
  • 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. 1.Clinical Research Center National Hospital Organization (NHO) Nagasaki Medical CenterOmura, NagasakiJapan
  2. 2.Department of HepatologyNagasaki University Graduate School of Biomedical SciencesOmura, NagasakiJapan
  3. 3.Department of Microbiology and ImmunologyHokkaido University Graduate School of MedicineSapporoJapan

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