title: Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-kappaB and -MAPK signaling pathways.
abstract: 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-kappaB 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 TLR2 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, suggests the involvement of TLRs in the development of chronic inflammatory cholangiopathies.
authors.affiliation: Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Komori
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takii
authors.forename: Takashi
authors.initials: T
authors.lastname: Kamihira
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mori
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Makiko
authors.initials: M
authors.lastname: Koyabu
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Hikaru
authors.initials: H
authors.lastname: Fujioka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yatsuhashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ishibashi
mesh_terms: D001649:Bile Duct Diseases / Q000503:physiopathology; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D013682:Teichoic Acids / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D013450:Sulfones; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid; D020929:Mitogen-Activated Protein Kinase Kinases