title: A lipid A analog inhibits LPS-induced cytokine expression and improves survival in endotoxemic mice.
abstract: It has recently been shown that inactive disaccharidic analogs of lipid A, an essential structure of lipopolysaccharide (LPS), may act as LPS antagonists which would be effective against septic shock induced by gram-negative bacteria endotoxin. In the present study we examined the inhibitory effect of DY-9973, a synthetic monosaccharidic lipid A analog, on LPS-induced cytokine expression in macrophages and lethal toxicity in mice. DY-9973 inhibited TNF-alpha production induced by LPS in human monocytes and monoblastic U937 cells. Expression of cytokine mRNAs such as TNF-alpha and IL-1 beta induced by LPS was inhibited by treatment with DY-9973 in U937 cells. Meanwhile, DY-9973 did not inhibit IL-1 beta-induced TNF-alpha production in U937 cells. TNF-alpha production induced by LPS or IL-1 beta was similarly inhibited by treatment with herbimycin, a tyrosine kinase inhibitor. Pretreatment with DY-9973 inhibited the elevation of serum TNF-alpha activity induced by the injection of LPS and reduced the lethal toxicity of LPS in BCG-primed mice. These results suggest that monosaccharidic lipid A analog such as DY-9973 can inhibit LPS-induced activation of macrophages and that it reduces lethal toxicity of LPS.
authors.affiliation: New Product Research Laboratories I, Daiichi Pharmaceutical Co., Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Someya
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutomi
authors.forename: T
authors.initials: T
authors.lastname: Soga
authors.forename: K
authors.initials: K
authors.lastname: Akahane
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000187:drug effects; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides; D016403:Lymphoma, Large B-Cell, Diffuse; D051379:Mice; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D016207:Cytokines; C104124:DY 9973; D007375:Interleukin-1; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha