A novel inhibitory peptide of Toll-like receptor signaling limits lipopolysaccharide-induced production of inflammatory mediators and enhances survival in mice

Sepsis resulting from gram-negative bacterial infections is characterized by an excessive inflammatory immune response initiated by exposure of the host innate immune system to either bacteria or bacterial products, primarily lipopolysaccharide (LPS). Engagement of the Toll-like receptor (TLR) 4 on...

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Bibliographic Details
Published in:Shock (Augusta, Ga.) Ga.), 2007-04, Vol.27 (4), p.364-369
Main Authors: Tsung, Allan, McCoy, Sharon L, Klune, John R, Geller, David A, Billiar, Timothy R, Hefeneider, Steven H
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Cells, Cultured
Coculture Techniques
Cytokines - antagonists & inhibitors
Cytokines - biosynthesis
Female
Inflammation Mediators - antagonists & inhibitors
Inflammation Mediators - physiology
Lipopolysaccharides - antagonists & inhibitors
Lipopolysaccharides - pharmacology
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Molecular Sequence Data
Peptides - genetics
Peptides - physiology
Sepsis - mortality
Sepsis - pathology
Sepsis - prevention & control
Signal Transduction - physiology
Survival
Toll-Like Receptors - physiology
Viral Proteins - physiology
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Summary:Sepsis resulting from gram-negative bacterial infections is characterized by an excessive inflammatory immune response initiated by exposure of the host innate immune system to either bacteria or bacterial products, primarily lipopolysaccharide (LPS). Engagement of the Toll-like receptor (TLR) 4 on immune cells by LPS induces production of inflammatory mediators, leading to tissue damage. We recently identified a peptide, termed P13, which was previously shown to be a potent inhibitor of in vitro TLR signaling. In this study, we demonstrate that the use of this novel peptide significantly reduces the in vitro production of inflammatory mediators seen after exposure of hepatocytes/nonparenchymal cell cocultures and endothelial cells to LPS. In addition, in vivo treatment of mice with this peptide was effective at inhibiting LPS-induced production of inflammatory mediators and significantly limited liver damage. Peptide treatment significantly increased survival of LPS-/D-galactosamine-treated mice and mice treated with high-dose LPS. These results demonstrated the therapeutic potential of peptide P13 to limit an LPS-induced inflammatory response and enhance survival in murine models of inflammation.
ISSN:1073-2322
DOI:10.1097/01.shk.0000239773.95280.2c