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

Journal Article · Fri Oct 17 04:00:00 EDT 2008 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2008.07.150· OSTI ID:21143901

Schnabl, Bernd ^[1]; Brandl, Katharina; Fink, Marina; Gross, Philipp ^[2]; Taura, Kojiro ^[1]; Gaebele, Erwin; Hellerbrand, Claus; Falk, Werner ^[2]

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1. Department of Medicine, University of California San Diego, 9500 Gilman Drive, MC0702, La Jolla, CA 92093 (United States)
2. Department of Internal Medicine I, University of Regensburg (Germany)

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, 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.

• OSTI ID: 21143901
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 375; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
FIBROSIS
GROWTH FACTORS
IN VIVO
INFLAMMATION
INJURIES
LIGANDS
LIVER
MICE
MONOCYTES
MUTANTS
RECEPTORS
SECRETION