Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-κB and -MAPK signaling pathways

Terufumi Yokoyama, Atsumasa Komori, Minoru Nakamura, Yasushi Takii, Takashi Kamihira, Shinji Shimoda, Tsuyoshi Mori, Shinsuke Fujiwara, Makiko Koyabu, Ken Taniguchi, Hikaru Fujioka, Kiyoshi Migita, Hiroshi Yatsuhashi, Hiromi Ishibashi

Research output: Contribution to journalArticlepeer-review

125 Citations (Scopus)


Background: Human intrahepatic biliary epithelial cells (HIBECs) may play active roles in both the innate and adaptive immune responses. Little is known, however, about the role of toll-like receptors (TLRs) on HIBECs in inflammatory cholangiopathies. Methods: The expression of TLR1-9 and the biological responses to their ligands, lipopolysaccharide (LPS) or lipoteichoic acid (LTA), were studied in cultured HIBECs by reverse transcription-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay. Results: HIBECs constitutively expressed transcripts encoding TLR1-6 and 9, as well as myeloid differentiation factor 88 (MyD88), MD2, and CD14. Stimulation of HIBECs with LPS resulted in translocation of NF-κB subunits from the cytoplasmic to the nuclear fraction, followed by increased secretion of a variety of chemokines/cytokines, including interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and IL-6. Treatment with BAY11-7082 efficiently inhibited the LPS-induced transcription and secretion of these chemokines/cytokines. In HIBECs, the mitogen-activated protein kinases (MAPKs) were also activated by LPS stimulation. These results indicated that LPS activates HIBECs via a TLR4-MyD88-dependent pathway. Stimulation of HIBECs with LTA induced the secretion of a similar profile of cytokines/chemokines via a TLR2-MyD88-dependent pathway. Conclusions: In HIBECs, at least TL R2 and 4 are capable of mediating innate immune system function in vitro. This result, in conjunction with our recent finding that TLR4 expression is increased in biliary epithelial cells in primary biliary cirrhosis, suggest the involvement of TLRs in the development of chronic inflammatory cholangiopathies.

Original languageEnglish
Pages (from-to)467-476
Number of pages10
JournalLiver International
Issue number4
Publication statusPublished - May 2006

All Science Journal Classification (ASJC) codes

  • Hepatology


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