A TLR4/MD2 fusion protein inhibits LPS-induced pro-inflammatory signaling in hepatic stellate cells.
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.
Schnabl
Bernd
B
Department of Medicine, University of California San Diego, 9500 Gilman Drive, MC0702, La Jolla, CA 92093, USA. beschnabl@ucsd.edu
Brandl
Katharina
K
Fink
Marina
M
Gross
Philipp
P
Taura
Kojiro
K
Gäbele
Erwin
E
Hellerbrand
Claus
C
Falk
Werner
W
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000235:genetics / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000276:immunology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000276:immunology; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000627:therapeutic use*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000627:therapeutic use*
D018925:Chemokines; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4