A novel inhibitory peptide of Toll-like receptor signaling limits LPS-induced production of inflammatory mediators and enhances survival in mice (89.12)

Abstract

Abstract 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 LPS. Engagement of the TLR4 receptor 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 use of this novel peptide significantly reduces the in vitro production of inflammatory mediators seen after exposure of hepatocytes/NPC co-cultures 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 demonstrate the therapeutic potential of peptide P13 to limit an LPS-induced inflammatory response and enhance survival in models of inflammation. This study was supported by NIH SBIR 1R43AI065000-01A1