Induction of TNF-alpha and MnSOD by endotoxin: effect of E5531, a synthetic non-toxic lipid A analog

E5531, a synthetic lipid A analog, has been shown to inhibit endotoxin (lip opolysaccharide, LPS)-induced tumor necrosis factor-alpha (TNF-alpha) produ ction by human monocytes and murine macrophages. Whether it also inhibits L PS induction of manganese superoxide dismutase (MnSOD) is not clear. In the current study, we demonstrated that E5531, while having no effect on TNF-a lpha and MnSOD mRNAs by itself, markedly inhibited LPS- and lipid A-, but n ot TNF-alpha-, induced increases in TNF-alpha and MnSOD mRNAs in human mono cytes. In contrast, E5531 at concentrations and conditions that markedly in hibit LPS-induced increases in TNF-alpha and MnSOD mRNAs, and TNF-alpha pro duction by human monocytes, had no effect on murine peritoneal macrophages. These results demonstrate that E5531 is a potent LPS antagonist in human m onocytes. However, it does not show antagonist action against LPS in murine macrophages in the range of concentrations tested, suggesting that E5531 i s a more potent antagonist in humans than in mice.