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 (lipopolysaccharide, LPS)-induced tumor necrosis factor-alpha (TNF-alpha) production by human monocytes and murine macrophages. Whether it also inhibits LPS induction of manganese superoxide dismutase (MnSOD) is not clear. In the current study, we demonstrated that E5531, while having no effect on TNF-alpha and MnSOD mRNAs by itself, markedly inhibited LPS- and lipid A-, but not TNF-alpha-, induced increases in TNF-alpha and MnSOD mRNAs in human monocytes. In contrast, E5531 at concentrations and conditions that markedly inhibit LPS-induced increases in TNF-alpha and MnSOD mRNAs, and TNF-alpha production by human monocytes, had no effect on murine peritoneal macrophages. These results demonstrate that E5531 is a potent LPS antagonist in human monocytes. However, it does not show antagonist action against LPS in murine macrophages in the range of concentrations tested, suggesting that E5531 is a more potent antagonist in humans than in mice.
White
J E
JE
Research Service, Stratton VA Medical Center, Albany, NY 12208, USA.
Tsan
M F
MF
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000031:analogs & derivatives / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D008050:Lipid A; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C092845:E 5531; D013482:Superoxide Dismutase