A TLR4/MD2 fusion protein inhibits LPS-induced pro-inflammatory signaling in hepatic stellate cells

作者：Schnabl Bernd^*; Brandl Katharina; Fink Marina; Gross Philipp; Taura Kojiro; Gaebele Erwin; Hellerbrand Claus; Falk Werner

来源：Biochemical and Biophysical Research Communications, 2008, 375(2): 210-214.

DOI：10.1016/j.bbrc.2008.07.150

• LPS
• toll-like receptor
• hepatic stellate cells
• liver fibrosis

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 NF kappa B and JNK activation. TLR4/MD2 abolished LPS-induced secretion of IL-6, IL-8, MCPI, 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.

• 出版日期2008-10-17