AGONISTS AND ANTAGONISTS FOR LIPOPOLYSACCHARIDE-INDUCED CYTOKINES

Agonistic and antagonistic properties of LPS and partial structures in the induction of cytokines are reviewed. Studies on structure-activit y relationships of LPS and lipid A with human mononuclear cells reveal that S- and notably R-form LPS are very potent cytokine inducers. Syn thetic E. coli lipid A is somewhat less active, whereas synthetic S. m innesota-type lipid A is significantly less active. Pentaacylated form s of lipid A are less potent than hexaacylated forms, and tetraacylate d synthetic precursor la and bisacylated disaccharides and monosacchar ides are completely inactive, indicating that a structure-dependent hi erarchy of LPS and lipid A partial structures determines the monokine- inducing capacity in human mononuclear cells. Precursor Ia is a potent LPS antagonist. The mechanism of its inhibitory activity is shown to be due to competitive binding to cellular binding sites (receptors). P roinflammatory and antiinflammatory cytokines, receptor antagonists, a nd soluble cytokine receptors influence the cytokine-inducing activity of LPS, suggesting a complex regulatory network.