Chemically detoxified lipid A precursor derivatives antagonize the TNF-alpha-inducing action of LPS in both murine macrophages and a human macrophage cell line.
The chemically synthesized disaccharide precursor of lipid A (406) has been demonstrated to reduce its activity in mice by an order of 10(5) or more by replacing the hydroxyl groups with succinyl or acetyl residues. In the present study, these chemically detoxified synthetic lipid A precursors were found to antagonize the LPS action of inducing TNF-alpha in both murine peritoneal macrophages and in human monocyte-macrophage cell line THP-1. These preparations were found to antagonize the induction of TNF-alpha in murine macrophages by both stimulants of LPS and untreated 406, which acts as an agonist in the murine system, in a dose-dependent manner. Complete inhibition by succinylated 406 occurred at 10-fold excesses of the antagonist. Succinylated precursor also antagonized the TNF-alpha-inducing action of LPS in human cell line THP-1. The precursor itself also exhibited antagonism in this assay. The activity of the succinylated 406, however, was much more potent than that of the unmodified precursor. These derivatives do not inhibit either the Limulus gelation activity of LPS, or the induction of TNF-alpha in macrophages by zymosan, indicating that the inhibition is not caused by molecular interaction and that the inhibition is specific to LPS action. These findings suggest common features in murine macrophage and human monocytic cell receptors. They also suggest the importance of the substituents on the hydroxyl groups of 3-hydroxy fatty acids of the nonreducing glucosamine of lipid A for the activity and for transformation to the antagonistic structure.
Tanamoto
K
K
Division of Microbiology, National Institute of Health Sciences, Tokyo, Japan.
D000818:Animals; D002460:Cell Line; D005260:Female; D006017:Glycolipids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D006017:Glycolipids; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C040142:lipid A precursors, bacterial