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Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells

Authors
 Yong-Han Paik  ;  Robert F. Schwabe  ;  David A. Brenner  ;  Christian Jobin  ;  Maria P. Russo  ;  Ramón Bataller 
Citation
 HEPATOLOGY, Vol.37(5) : 1043-1055, 2003 
Journal Title
 HEPATOLOGY 
ISSN
 0270-9139 
Issue Date
2003
MeSH
Animals ; Blood Proteins/pharmacology ; Cells, Cultured ; Chemokine CCL2/metabolism ; Drosophila Proteins* ; Hepatocytes/cytology ; Hepatocytes/physiology* ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Interleukin-8/metabolism ; JNK Mitogen-Activated Protein Kinases ; Lipopolysaccharide Receptors/genetics ; Lipopolysaccharide Receptors/metabolism ; Lipopolysaccharides/pharmacology* ; Liver Cirrhosis/immunology ; Liver Cirrhosis/metabolism* ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism* ; Mice ; Mice, Inbred C3H ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism* ; Signal Transduction/drug effects ; Signal Transduction/immunology* ; Toll-Like Receptor 4 ; Toll-Like Receptors ; Transcription Factor AP-1/metabolism ; Up-Regulation/drug effects ; Up-Regulation/immunology ; Vascular Cell Adhesion Molecule-1/metabolism
Keywords
12717385
Abstract
Bacterial lipopolysaccharide (LPS) stimulates Kupffer cells and participates in the pathogenesis of alcohol-induced liver injury. However, it is unknown whether LPS directly affects hepatic stellate cells (HSCs), the main fibrogenic cell type in the injured liver. This study characterizes LPS-induced signal transduction and proinflammatory gene expression in activated human HSCs. Culture-activated HSCs and HSCs isolated from patients with hepatitis C virus-induced cirrhosis express LPS-associated signaling molecules, including CD14, toll-like receptor (TLR) 4, and MD2. Stimulation of culture-activated HSCs with LPS results in a rapid and marked activation of NF-κB, as assessed by in vitro kinase assays for IκB kinase (IKK), IκBα steady-state levels, p65 nuclear translocation, NF-κB-dependent luciferase reporter gene assays, and electrophoretic mobility shift assays. Lipid A induces NF-κB activation in a similar manner. Both LPS- and lipid A-induced NF-κB activation is blocked by preincubation with either anti-TLR4 blocking antibody (HTA125) or Polymyxin B. Lipid A induces NF-κB activation in HSCs from TLR4-sufficient (C3H/OuJ) mice but not from TLR4-deficient (C3H/HeJ) mice. LPS also activates c-Jun N-terminal kinase (JNK), as assessed by in vitro kinase assays. LPS up-regulates IL-8 and MCP-1 gene expression and secretion. LPS-induced IL-8 secretion is completely inhibited by the IκB super repressor (Ad5IκB) and partially inhibited by a specific JNK inhibitor, SP600125. LPS also up-regulates cell surface expression of ICAM-1 and VCAM-1. In conclusion, human activated HSCs utilize components of TLR4 signal transduction cascade to stimulate NF-κB and JNK and up-regulate chemokines and adhesion molecules. Thus, HSCs are a potential mediator of LPS-induced liver injury.
Full Text
http://onlinelibrary.wiley.com/doi/10.1053/jhep.2003.50182/abstract
DOI
10.1053/jhep.2003.50182
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Paik, Yong Han(백용한)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/113405
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