Endotoxin antagonism by a synthetic lipid A analogue, DT-5461, with low endotoxicity in human peripheral blood monocytes.
We examined the molecular mechanism of DT-5461-induced LPS antagonism in human peripheral blood monocytes. Dose-response studies revealed that LPS-induced IL-1 and TNF-alpha production was apparently totally suppressed in a competitive manner by a 10-fold excess of DT-5461. A 10-fold excess of DT-5461 significantly blocked the binding of FITC-LPS to the monocytes. DT-5461 suppressed IL-1 and TNF-alpha mRNA expression in LPS-activated monocytes. Western blots showed that DT-5461 suppressed the LPS-induced tyrosine phosphorylation of p42mapk/ERK2. These results suggested that the competitive binding inhibition and repression of early intracellular signaling involved in DT-5461-mediated LPS antagonism.
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001667:Binding, Competitive; D002478:Cells, Cultured; D003470:Culture Media; D016895:Culture Media, Serum-Free; D004187:Disaccharides / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004926:Escherichia coli; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D007700:Kinetics; D008050:Lipid A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D003470:Culture Media; D016895:Culture Media, Serum-Free; D004187:Disaccharides; D004731:Endotoxins; D007375:Interleukin-1; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C077208:DT 5461