A novel synthetic lipid A analog with low endotoxicity, DT-5461, prevents lethal endotoxemia.
Bacterial endotoxin (lipopolysaccharide [LPS]) causes severe damage to the host organism as a result of excessive release of inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), from mononuclear phagocytes during gram-negative bacterial infection. We evaluated the ability of a novel synthetic lipid A analog with low endotoxicity, DT-5461, to antagonize LPS-induced IL-1 and TNF-alpha production in cells of monocyte/macrophage lineage and examined the protective effect of DT-5461 against lethal endotoxic shock in mice. The IL-1- or TNF-alpha-inducing activity of DT-5461 is 100,000 to 10,000 times less active than that of Escherichia coli LPS (EcLPS) or synthetic lipid A. DT-5461 significantly inhibited EcLPS-induced IL-1 and TNF-alpha release when murine peritoneal macrophages were incubated with DT-5461 2 h prior to EcLPS stimulation at the same concentration (1 microgram/ml). The antagonistic effect of DT-5461 on the production of IL-1 and TNF-alpha induced by EcLPS occurred in a concentration-dependent manner. DT-5461 also inhibited IL-1 and TNF-alpha induction when murine peritoneal macrophages were stimulated by LPS from Salmonella typhimurium or synthetic lipid A, as well as by EcLPS, but not by muramyl dipeptides. This indicated that DT-5461 specifically antagonized the action of LPS. DT-5461 also antagonized EcLPS-mediated activation of human peripheral blood monocytes. DT-5461 blocked the binding of fluorescein isothiocyanate-labelled LPS to murine peritoneal macrophages as well as it did the binding of EcLPS and synthetic lipid A, i.e., in a concentration-dependent fashion. Injection of DT-5461 2 h before EcLPS challenge prevented the production of serum IL-1 and TNF-alpha in D-galactosamine-treated mice. Furthermore, this treatment modality protected mice against LPS-induced lethal toxicity. This study suggests that DT-5461 possesses a potent LPS antagonistic effect and may be useful in a protective strategy against lethal endotoxemia caused by gram-negative bacterial infection.
Sato
K
K
Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Yoo
Y C
YC
Fukushima
A
A
Saiki
I
I
Takahashi
T A
TA
Fujihara
M
M
Tono-Oka
S
S
Azuma
I
I
D000818:Animals; D004187:Disaccharides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D008050:Lipid A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000187:drug effects; D012772:Shock, Septic / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004187:Disaccharides; D007375:Interleukin-1; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; C077208:DT 5461; D005688:Galactosamine