Abstract
Activated hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis. In injured liver they are the main extracellular matrix protein producing cell type and further perpetuate hepatic injury by secretion of pro-inflammatory mediators. Since LPS-mediated signaling through toll-like receptor 4 (TLR4) has been identified as key fibrogenic signal in HSCs we aimed to test TLR4 as potential target of therapy via ligand-binding soluble receptors. Incubation of human HSCs with a fusion protein between the extracellular domain of TLR4 and MD2 which binds LPS inhibited LPS-induced NFkappaB and JNK activation. TLR4/MD2 abolished LPS-induced secretion of IL-6, IL-8, MCP1, and RANTES in HSCs. In addition, TLR4/MD2 fused to human IgG-Fc neutralized LPS activity. Since TLR4 mutant mice are resistant to liver fibrosis, the TLR4/MD2 soluble receptor might represent a new therapeutic molecule for liver fibrogenesis in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Chemokines / antagonists & inhibitors
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Chemokines / biosynthesis
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Humans
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / therapeutic use
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Immunoglobulin G / genetics
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Immunoglobulin G / therapeutic use
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Lipopolysaccharides / antagonists & inhibitors*
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Lipopolysaccharides / immunology
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Liver Cirrhosis / drug therapy*
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Liver Cirrhosis / immunology
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Lymphocyte Antigen 96 / genetics
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Lymphocyte Antigen 96 / therapeutic use*
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MAP Kinase Kinase 4 / metabolism
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Mice
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NF-kappa B / metabolism
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Protein Structure, Tertiary / genetics
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / therapeutic use*
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Signal Transduction
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / therapeutic use*
Substances
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Chemokines
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Immunoglobulin Fc Fragments
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Immunoglobulin G
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Lipopolysaccharides
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Lymphocyte Antigen 96
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NF-kappa B
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Recombinant Fusion Proteins
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Toll-Like Receptor 4
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MAP Kinase Kinase 4