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

Eur J Biochem. 2000 Apr;267(7):2008-13. doi: 10.1046/j.1432-1327.2000.01204.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbohydrate Sequence
  • Endotoxins / pharmacology
  • Humans
  • Interleukin-6 / biosynthesis
  • Lipid A / chemistry*
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / metabolism*
  • Lipopolysaccharides / pharmacology
  • Molecular Sequence Data
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • X-Ray Diffraction

Substances

  • Endotoxins
  • Interleukin-6
  • Lipid A
  • Lipopolysaccharides