ORIGINAL ARTICLE

Interferon  accelerates NF-B activation of biliary epithelial cells induced by Toll-like receptor and ligand interaction

K Harada, K Isse and Y Nakanuma

Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920–8640, Japan

Correspondence to:
Correspondence to:
Dr Y Nakanuma
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920–8640, Japan; pbcpsc{at}kenroku.kanazawa-u.ac.jp

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 B (NF-B) activation.

Aims: To examine the presence of TLRs in human BECs and the influence of cytokines and PAMPs on TLR expression and NF-B 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 (IFN) was evaluated by NF-B 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 IFN, and TLR2 was upregulated by tumour necrosis factor . Interleukins 4 and 6 failed to induce TLR upregulation. Interestingly, preincubation with IFN synergistically increased the upregulation of NF-B 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.

Abbreviations: BEC, biliary epithelial cell; EBO, extrahepatic biliary obstruction; HCV-LC, hepatitis C virus related liver cirrhosis; ICC, intrahepatic cholangiocarcinoma; IFN, interferon ; IFNR, interferon receptor; IL, interleukin; IL-4/5/6R, interleukin 4/5/6 receptor; LPS, lipopolysaccharide; NF-B, nuclear factor B; 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; TNF, tumour necrosis factor ; TNFR, tumour necrosis factor receptor

Keywords: innate immunity; biliary epithelial cells; Toll-like receptor; pathogen associated molecular patterns

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