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Interferon γ accelerates NF-κB activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction
  1. K Harada,
  2. K Isse,
  3. Y Nakanuma
  1. Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920–8640, Japan
  1. Correspondence to:
 Dr Y Nakanuma
 Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920–8640, Japan; pbcpsc{at}


Background: The Toll-like receptor (TLR) family recognises pathogen associated molecular patterns (PAMPs) and plays a pivotal role in the innate immune response. Biliary epithelial cells (BECs) lining the intrahepatic bile ducts are potentially exposed to bacterial components in bile, and murine BECs possess TLRs that recognise PAMPs, resulting in nuclear factor κB (NF-κB) activation.

Aims: To examine the presence of TLRs in human BECs and the influence of cytokines and PAMPs on TLR expression and NF-κB activation.

Methods: The expression of TLR2–5, MD-2, MyD88, and IRAK1 was examined in human liver tissue and cultured BECs by immunohistochemistry or reverse transcription polymerase chain reaction. The influence of PAMPs (peptidoglycan and lipopolysaccharide) in cultured cells preincubated with interferon γ (IFNγ) was evaluated by NF-κB activation.

Results: TLR2–5, MyD88, and IRAK-1 proteins were detectable in BECs of the intrahepatic biliary tree in human liver tissue. TLR2–5, MD-2, MyD88, and IRAK-1 mRNA was demonstrated in human cultured BECs. The expression of these TLRs was upregulated by IFNγ, and TLR2 was upregulated by tumour necrosis factor α. Interleukins 4 and 6 failed to induce TLR upregulation. Interestingly, preincubation with IFNγ synergistically increased the upregulation of NF-κB induced by PAMPs in cultured BECs.

Conclusion: These results suggest that the TLR family is present in human biliary cells and participates in the innate immunity of the intrahepatic biliary tree. Disordered regulation of TLRs after intracellular signalling by cytokines and PAMPs may be involved in immune mediated biliary diseases.

  • BEC, biliary epithelial cell
  • EBO, extrahepatic biliary obstruction
  • HCV-LC, hepatitis C virus related liver cirrhosis
  • ICC, intrahepatic cholangiocarcinoma
  • IFNγ, interferon γ
  • IFNγR, interferon γ receptor
  • IL, interleukin
  • IL-4/5/6R, interleukin 4/5/6 receptor
  • LPS, lipopolysaccharide
  • NF-κB, nuclear factor κB
  • PAMP, pathogen associated molecular pattern
  • PBC, primary biliary cirrhosis
  • PCR, polymerase chain reaction
  • PGN, peptidoglycan
  • RT, reverse transcription
  • Th1, T helper type 1
  • TLR, Toll-like receptor
  • TNFα, tumour necrosis factor α
  • TNFR, tumour necrosis factor receptor
  • innate immunity
  • biliary epithelial cells
  • Toll-like receptor
  • pathogen associated molecular patterns

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