Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion

Lipopolysaccharide (LPS) represents a major virulence factor of Gram-negati ve bacteria ('endotoxin') that can cause septic shock in mammals including man. The lipid anchor of LPS to the outer membrane, lipid A, has a peculiar chemical structure, harbours the 'endotoxic principle' of LPS and is respo nsible for the expression of pathophysiological effects. Chemically modifie d lipid A can be endotoxically inactive, but may express strong antagonisti c activity against LPS, a property that can be utilized in antisepsis treat ment. We show here that these different biological activities are directly correlated with the molecular shape of lipid A. Only (hexaacyl) lipid A wit h a conical/concave shape, the cross-section of the hydrophobic region bein g larger than that of the hydrophilic region, exhibited strong interleukin- 6 (IL-6)-inducing capacity. Most strikingly, a correlation between a cylind rical molecular shape of lipid A and antagonistic activity was established: IL-6 induction by enterobacterial LPS was inhibited by cylindrically shape d lipid A except for compounds with reduced headgroup charge. The antagonis tic action is interpreted by assuming that lipid A molecules intercalate in to the cytoplasmic membrane of mononuclear cells, and subsequently blocking of the putative signaling protein by the lipid A with cylindrical shape.