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.