Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology (Baltimore, Md.) [Hepatology] Journal article

Title	Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells.
Author(s)	Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA
Institution	Department of Medicine, University of North Carolina at Chapel Hill, USA.
Source	Hepatology 2003 May; 37(5):1043-55.
MeSH	Animals Antigens, CD14 Blood Proteins Cells, Cultured Drosophila Proteins Hepatocytes Humans Intercellular Adhesion Molecule-1 Interleukin-8 JNK Mitogen-Activated Protein Kinases Lipopolysaccharides Liver Cirrhosis Membrane Glycoproteins Mice Mice, Inbred C3H Mitogen-Activated Protein Kinases Monocyte Chemoattractant Protein-1 NF-kappa B Receptors, Cell Surface Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Signal Transduction Toll-Like Receptor 4 Toll-Like Receptors Transcription Factor AP-1 Up-Regulation Vascular Cell Adhesion Molecule-1
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-kappaB, as assessed by in vitro kinase assays for IkappaB kinase (IKK), IkappaBalpha steady-state levels, p65 nuclear translocation, NF-kappaB-dependent luciferase reporter gene assays, and electrophoretic mobility shift assays. Lipid A induces NF-kappaB activation in a similar manner. Both LPS- and lipid A-induced NF-kappaB activation is blocked by preincubation with either anti-TLR4 blocking antibody (HTA125) or Polymyxin B. Lipid A induces NF-kappaB 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 IkappaB super repressor (Ad5IkappaB) 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-kappaB and JNK and up-regulate chemokines and adhesion molecules. Thus, HSCs are a potential mediator of LPS-induced liver injury.
Language	eng
Pub Type(s)	Journal Article
PubMed ID	12717385

Advertise on this site.