Someya K, Tsutomi Y, Soga T, Akahane K
New Product Research Laboratories I, Daiichi Pharmaceutical Co., Tokyo, Japan.
Immunopharmacol Immunotoxicol. 1996 Nov;18(4):477-95. doi: 10.3109/08923979609052749.
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.
脂多糖（LPS）的必需结构脂多糖A的无活性二糖类似物最近已被证明可作为LPS拮抗剂，对革兰氏阴性菌内毒素诱导的脓毒症休克有效。在本研究中，我们检测了合成的单糖脂多糖A类似物DY-9973对巨噬细胞中LPS诱导的细胞因子表达和小鼠致死毒性的抑制作用。DY-9973抑制了LPS在人单核细胞和单核细胞U937细胞中诱导的TNF-α产生。在U937细胞中，用DY-9973处理可抑制LPS诱导的细胞因子mRNA如TNF-α和IL-1β的表达。同时，DY-9973不抑制IL-1β在U937细胞中诱导的TNF-α产生。LPS或IL-1β诱导的TNF-α产生同样被酪氨酸激酶抑制剂除草菌素处理所抑制。用DY-9973预处理可抑制注射LPS诱导的血清TNF-α活性升高，并降低LPS对卡介苗致敏小鼠的致死毒性。这些结果表明，单糖脂多糖A类似物如DY-9973可抑制LPS诱导的巨噬细胞活化，并降低LPS的致死毒性。
