Induction by lipopolysaccharide of intracellular and extracellular interleukin 1 production: analysis with synthetic models

An attempt was made to identify the molecular structures that are present in bacterial LPS and induce the production of intracellular and extracellular pools of IL 1 by peritoneal macrophages of the mouse and by human monocytes. Activities of glycolipids and carbohydrates prepared by synthesis, and structurally related to the hydrophobic (Lipid A) and to the polysaccharide (PS) regions of LPS were compared with those induced by Bordetella pertussis endotoxin and by fragments derived therefrom. Both isolated regions of this LPS (PS and Lipid A) were able to induce IL 1 synthesis by monocytes and macrophages. Among the synthetic glycolipids employed, propyl-2-deoxy-2-[(3R)-3-hydroxytetrade-canamido]-4-O-pho sph ono-6-O-tetradecanoyl-beta-D-glucopyranoside (glycolipid M9) induced IL 1 secretion more efficiently than Lipid A and LPS, whereas the amounts of intracellular IL 1 produced upon induction by these three substances were comparable. Macrophages from C3H/HeJ mice were unresponsive to Lipid A and to glycolipid M9, but produced IL 1 when incubated with PS or with a hydrophilic fragment isolated after methanolysis of the endotoxin. However, all synthetic derivatives of 3-deoxy-D-manno-2-octulosonic acid (KDO) used in this study failed to induce IL 1 production by both mouse macrophages and human monocytes. The implications of these findings for a more precise comprehension of the molecular mechanism of LPS-induced activation of macrophages, and the relations between the molecular structures required for the induction of IL 1 production vs cytostatic activity in macrophages, are discussed.