title: Definition of structural prerequisites for lipoteichoic acid-inducible cytokine induction by synthetic derivatives.
abstract: The controversy about the immune stimulatory properties of lipoteichoic acid (LTA) from Staphylococcus aureus was solved recently by showing decomposition and inactivation of LTA obtained by conventional purification strategies, as well as pronounced LPS contamination of commercial preparations. By introducing a novel preparation method, the structure of bioactive LTA was elucidated. This structure was confirmed by chemical synthesis. In this work, synthetic LTA derivatives were employed to study the structure-function relationship of cytokine induction in human monocytes. Synthetic LTA induced the same cytokine pattern as highly purified natural LTA. The gentiobiose core could be omitted without affecting bioactivity. The polyglycerophosphate backbone amplified the response to the lipid anchor ( approximately 100-fold) only when substituted with D-alanine, whereas alpha-D-N-acetylglucosamine substituents could be omitted. Replacing D-alanine substituents with L-alanine reduced the activity of the molecule at least 10-fold, indicating stereoselectivity. These results define for the first time the crucial patterns required for the immune recognition of LTA.
authors.affiliation: Biochemical Pharmacology and Department of Chemistry, University of Konstanz, Konstanz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Deininger
authors.forename: Andreas
authors.initials: A
authors.lastname: Stadelmaier
authors.forename: Sonja
authors.initials: S
authors.lastname: von Aulock
authors.forename: Siegfried
authors.initials: S
authors.lastname: Morath
authors.forename: Richard R
authors.initials: RR
authors.lastname: Schmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000409:Alanine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D004187:Disaccharides / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000502:physiology; D013211:Staphylococcus aureus / Q000737:chemistry / Q000276:immunology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013682:Teichoic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051193:Toll-Like Receptors
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004187:Disaccharides; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D013682:Teichoic Acids; D051193:Toll-Like Receptors; C026244:alanyl-lipoteichoic acid; C009900:lipoteichoic acid; C100052:gentiobiose; D000409:Alanine; D000117:Acetylglucosamine