A Lipid a Analog Inhibits LPS-Induced Cytokine Expression and Improves Survival in Endotoxemic Mice

AbstractIt 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-α production induced by LPS in human monocytes and monoblastic U937 cells. Expression of cytokine mRNAs such as TNF-α and IL-1 β induced by LPS was inhibited by treatment with DY-9973 in U937 cells. Meanwhile, DY-9973 did not inhibit IL-1β-induced TNF-α production in U937 cells. TNF-α production induced by LPS or IL-1 β was similarly inhibited by treatment with herbimycin, a tyrosine kinase inhibitor. Pretreatment with DY-9973 inhibited the elevation of serum TNF-α activity induced by the injection of LPS and reduced the lethal toxicity of LPS in BC...