Inhibitory effects of the peptide (CKPV)2 on endotoxin-induced host reactions
2006
Background α-Melanocyte stimulating hormone (α-MSH) is an endogenous peptide that has remarkable anti-inflammatory and antimicrobial effects. These activities have been traced to the C-terminal tripeptide Lys-Pro-Val (KPV). A dimer composed of two KPV sequences connected with a Cys-Cys linker, (CKPV) 2 , is currently under clinical investigation for antimicrobial use. The present research was designed to evaluate effects of (CKPV) 2 on endotoxin-induced host reactions in vitro and in vivo . Materials and methods Effects of (CKPV) 2 , KPV, and [Nle4-dPhe7]-α-MSH (NDP-α-MSH) on tumor necrosis factor α (TNF-α) production were determined: 1) in human peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) in vitro , and 2) in rats injected with LPS i.v. and sacrificed at 1 h. In additional experiments, dialysis peritonitis was induced in rats by adding LPS to dialysis fluid. Net ultrafiltrate was calculated and concentrations of nitrite (NO 2 − ) and TNF-α were measured in blood and peritoneal fluid at 7 h. Results (CKPV) 2 inhibited TNF-α production by LPS-stimulated human PBMC. This small peptide was as effective as NDP-α-MSH and more potent than KPV. Similar effectiveness was observed in vivo : 1 h after LPS injection, the large increase in circulating TNF-α was markedly reduced by (CKPV) 2 treatment. In LPS-induced peritonitis, (CKPV) 2 restored net ultrafiltrate to control values and significantly inhibited concentrations of TNF-α and NO 2 − both in plasma and in dialysate. Conclusions The remarkable capacity of (CKPV) 2 to inhibit endotoxin-induced host reactions suggests that it may be useful in treatment of inflammatory disorders.
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