Biological activities of lipopolysaccharides are determined by the shape of their lipid a portion
Schromm, Andra B.
Moran, Anthony P.
Koch, Michel H. J.
Rietschel, Ernst TH.
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Schromm, Andra B. Brandenburg, Klaus; Loppnow, Harald; Moran, Anthony P.; Koch, Michel H. J.; Rietschel, Ernst TH.; Seydel, Ulrich (2000). Biological activities of lipopolysaccharides are determined by the shape of their lipid a portion. European Journal of Biochemistry 267 (7), 2008-2013
Lipopolysaccharide (LPS) represents a major virulence factor of Gram-negative 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 responsible for the expression of pathophysiological effects. Chemically modified lipid A can be endotoxically inactive, but may express strong antagonistic activity against LPS, a property that can be utilized in antisepsis treatment. We show here that these different biological activities are directly correlated with the molecular shape of lipid A. Only (hexaacyl) lipid A with a conical/concave shape, the cross-section of the hydrophobic region being larger than that of the hydrophilic region, exhibited strong interleukin-6 (IL-6)-inducing capacity. Most strikingly, a correlation between a cylindrical molecular shape of lipid A and antagonistic activity was established: IL-6 induction by enterobacterial LPS was inhibited by cylindrically shaped lipid A except for compounds with reduced headgroup charge. The antagonistic action is interpreted by assuming that lipid A molecules intercalate into the cytoplasmic membrane of mononuclear cells, and subsequently blocking of the putative signaling protein by the lipid A with cylindrical shape.