Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK-M
Article first published online: 10 AUG 2006
Volume 26, Issue 8, pages 935–942, October 2006
How to Cite
Harada, K., Isse, K., Sato, Y., Ozaki, S. and Nakanuma, Y. (2006), Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK-M. Liver International, 26: 935–942. doi: 10.1111/j.1478-3231.2006.01325.x
- Issue published online: 5 SEP 2006
- Article first published online: 10 AUG 2006
- Received 22 March 2006,accepted 14 June 2006
- biliary epithelial cells;
- endotoxin tolerance;
- innate immunity;
- Toll-like receptor
Abstract: Background/Aim: Biliary epithelial cells possess an innate immune system consisting of Toll-like receptors (TLRs). Although the human bile contains lipopolysaccharide (LPS) in normal as well as diseased livers, LPS physiologically does not elicit an inflammatory response in the biliary tree. This absence of a response to LPS could be due to the ‘endotoxin tolerance’ speculated to maintain innate immune homeostasis in organs. Our aim here is to clarify the presence and molecular mechanisms of endotoxin tolerance of biliary epithelium.
Methods and Results: In nuclear factor-κB (NF-κB)-DNA binding assays using three-cultured human intrahepatic biliary epithelial cell (HIBEC) lines, all the cells responded to LPS (TLR4 ligand) by activating NF-κB, but pretreatment with LPS for 24 h effectively induced tolerance against any subsequent stimulation with LPS (endotoxin tolerance). This tolerance was also induced by pretreatment with Pam3Cys-Ser-(Lys)4 trihydrochloride (Pam3CKS4, TLR1/2 ligand). Then, real-time polymerase chain treaction and Western blotting revealed that LPS treatment upregulated the expression of IRAK-M (a negative regulator of TLR signaling), but did not affect interleukin-1 receptor-associated kinase-1 (IRAK-1, an essential molecule of TLR signaling), in HIBECs. Moreover, immunohistochemistry revealed that IRAK-M was diffusely expressed in intrahepatic bile ducts.
Conclusions: This study showed that the mechanism of endotoxin tolerance exists in the intrahepatic biliary tree and is possibly induced by the expression of IRAK-M in the intrahepatic biliary epithelium, suggesting that the endotoxin tolerance is important in maintaining innate immune biliary homeostasis.