title: Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion.
abstract: 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.
authors.affiliation: The Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, MA, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Schromm
authors.forename: K
authors.initials: K
authors.lastname: Brandenburg
authors.forename: H
authors.initials: H
authors.lastname: Loppnow
authors.forename: A P
authors.initials: AP
authors.lastname: Moran
authors.forename: M H
authors.initials: MH
authors.lastname: Koch
authors.forename: E T
authors.initials: ET
authors.lastname: Rietschel
authors.forename: U
authors.initials: U
authors.lastname: Seydel
mesh_terms: D002240:Carbohydrate Sequence; D004731:Endotoxins / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008050:Lipid A / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014961:X-Ray Diffraction
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D008050:Lipid A; D008070:Lipopolysaccharides