The novel beta-defensin DEFB123 prevents lipopolysaccharide-mediated effects in vitro and in vivo.
Defensins are a family of secreted antimicrobial peptides proposed to directly interfere with bacterial membranes. Here we show a functional analysis of the novel beta-defensin DEFB123. A peptide comprising the beta-defensin core region was synthesized and used for our analysis. Like other beta-defensins, DEFB123 exerted antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, which was assessed by microbroth dilution assay and radial diffusion zone assay. In addition, the peptide showed lipopolysaccharide (LPS)-binding activity in a Limulus amoebocyte lysate (LAL) assay. Moreover, DEFB123 prevented LPS-induced tumor necrosis factor (TNF)-alpha secretion in a murine monocyte cell line (RAW264.7). Accordingly, DEFB123 abolished LPS-mediated MAPK induction in these cells. Protection against LPS-mediated effects was then investigated in a murine model of acute sepsis. Our experiments show that synthetic beta-defensin DEFB123 prevents LPS-induced mortality in C57BL/6 mice in a therapeutic approach. We propose that the physiological role of beta-defensins may include interference with LPS-action on macrophages, a function formerly thought to be restricted to the family of cathelicidins, a structurally unrelated group of antimicrobial peptides.
Motzkus
Dirk
D
IPF PharmaCeuticals, Hannover, Germany.
Schulz-Maronde
Sandra
S
Heitland
Aleksandra
A
Schulz
Axel
A
Forssmann
Wolf-Georg
WG
Jübner
Martin
M
Maronde
Erik
E
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D004336:Drug Antagonism; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy / Q000401:mortality; D023083:beta-Defensins / Q000737:chemistry / Q000502:physiology*
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D023083:beta-Defensins