A novel lipid A from Halomonas magadiensis inhibits enteric LPS-induced human monocyte activation.
Lipopolysaccharide (LPS) endotoxin is the bacterial product responsible for the clinical syndrome of Gram-negative septicemia and endotoxic shock. During sepsis, microbial antigens, such as LPS, activate monocytes and macrophages to produce several pro-inflammatory cytokines, among which tumor necrosis factor-alpha (TNF-alpha) appears to be very important for the development of endotoxic shock. The endotoxic properties of LPS principally reside in the lipid A (LIP A) component, which is the primary immunostimulatory center of Gram-negative bacteria. In recent years there has been a continuous effort to identify molecules able to antagonize the deleterious effects of endotoxic shock. In this study we show that a novel LIP A fraction from the LPS of Halomonas magadiensis (Hm), a Gram-negative extremophilic and alkaliphilic bacterium, significantly inhibits the synthesis of TNF-alpha by human monocytes activated by Escherichia coli LPS. LIP A from Hm exerts these effects by interfering with E. coli LPS for activation of Toll-like receptor 4 expressed in human cells. This result defines Hm LIP A as a novel class of LPS antagonist whose structural features could be utilized for the design of compounds for the treatment of Gram-negative sepsis.
Ialenti
Armando
A
Department of Experimental Pharmacology, University of Naples Federico II, 80131 Naples, Italy.
Di Meglio
Paola
P
Grassia
Gianluca
G
Maffia
Pasquale
P
Di Rosa
Massimo
M
Lanzetta
Rosa
R
Molinaro
Antonio
A
Silipo
Alba
A
Grant
William
W
Ianaro
Angela
A
D002460:Cell Line; D004336:Drug Antagonism; D004926:Escherichia coli / Q000737:chemistry*; D020632:Halomonas / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008050:Lipid A / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013045:Species Specificity; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D008050:Lipid A; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha