Biological activities of lipopolysaccharides are determined by the shape of their lipid A portion.
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.
Schromm
A B
AB
The Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, MA, USA.
Brandenburg
K
K
Loppnow
H
H
Moran
A P
AP
Koch
M H
MH
Rietschel
E T
ET
Seydel
U
U
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
D004731:Endotoxins; D015850:Interleukin-6; D008050:Lipid A; D008070:Lipopolysaccharides