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
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorAtsumasa Komori
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorMinoru Nakamura
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorYasushi Takii
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorTakashi Kamihira
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorShinji Shimoda
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
Search for more papers by this authorTsuyoshi Mori
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorShinsuke Fujiwara
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorMakiko Koyabu
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorKen Taniguchi
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorHikaru Fujioka
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorKiyoshi Migita
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorHiroshi Yatsuhashi
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorHiromi Ishibashi
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorTerufumi Yokoyama
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorAtsumasa Komori
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorMinoru Nakamura
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorYasushi Takii
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorTakashi Kamihira
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorShinji Shimoda
Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
Search for more papers by this authorTsuyoshi Mori
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorShinsuke Fujiwara
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorMakiko Koyabu
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorKen Taniguchi
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Search for more papers by this authorHikaru Fujioka
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorKiyoshi Migita
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorHiroshi Yatsuhashi
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorHiromi Ishibashi
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan,
Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Search for more papers by this authorAbstract
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-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 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.
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