title: Toll-like receptor activation of human cells by synthetic triacylated lipid A-like molecules.
abstract: Recognition of microbial molecules by mammalian host receptors is essential to mount an immune response. Hexaacylated LPS is the prototypic example of a bacterial molecule recognized by the receptor complex TLR4/MD-2 with its lipid A moiety, whereas bacterial lipopeptides are recognized by TLR2. Here we show that a series of synthetic triacylated lipid A-like molecules are weak Toll-like receptor (TLR) agonists (mainly TLR2 agonists) but very potent TLR4/MD-2 antagonists (submicromolar range). Not only do they block human cell responses to LPS but also to whole gram-negative bacteria, and they inhibit the phagocytosis of gram-negative bacteria. These compounds may represent promising immunomodulatory agents.
authors.affiliation: Intensive Care Laboratory and Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva 14, Switzerland.
authors.forename: Irène
authors.initials: I
authors.lastname: Dunn-Siegrist
authors.forename: Pierre
authors.initials: P
authors.lastname: Tissières
authors.forename: Geneviève
authors.initials: G
authors.lastname: Drifte
authors.forename: Jacques
authors.initials: J
authors.lastname: Bauer
authors.forename: Stéphane
authors.initials: S
authors.lastname: Moutel
authors.forename: Jérôme
authors.initials: J
authors.lastname: Pugin
mesh_terms: D006090:Gram-Negative Bacteria / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D008050:Lipid A / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96 / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D007155:Immunologic Factors; C495377:LY96 protein, human; D008050:Lipid A; D051218:Lymphocyte Antigen 96; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4