title: Neisseria meningitidis lipid A mutant LPSs function as LPS antagonists in humans by inhibiting TLR 4-dependent cytokine production.
abstract: Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria and important in the induction of pro-inflammatory responses. Recently, novel LPS species derived from Neisseria meningitidis H44/76 by insertional inactivation of the lpxL1 and lpxL2 genes have been created with a lipid A portion consisting of five (penta-acylated lpxL1) or four (tetra-acylated lpxL2) fatty acids connected to the glucosamine backbone instead of six fatty acids in the wild-type LPS. We show that these mutant LPS-types are poor inducers of cytokines (tumor-necrosis factor-α, IL-1β, IL-10, IL-RA) in human mononuclear cells. Both penta- and tetra-acylated meningococcal LPSs were able to inhibit cytokine production by wild-type Escherichia coli or meningococcal LPS. Binding of FITC-labelled E. coli LPS TLR4 transfected Chinese hamster ovary (CHO) cells was inhibited by both mutant LPS-types. Experiments with CHO fibroblasts transfected with human CD14 and TLR4 showed that the antagonizing effect was dependent on the expression of human TLR4. In contrast to the situation in humans, lpxL1 LPS has agonistic activity for cytokine production in peritoneal macrophages of DBA mice, and exacerbated arthritis in murine collagen induced arthritis model. N. meningitidis lipid A mutant LPSs lpxL1 and lpxL2 function as LPS antagonists in humans by inhibiting TLR4-dependent cytokine production but have agonistic activity in mice.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Centre, The Netherlands. t.sprong@aig.umcn.nl
authors.forename: Tom
authors.initials: T
authors.lastname: Sprong
authors.forename: Peter van der
authors.initials: Pv
authors.lastname: Ley
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: Leo
authors.initials: L
authors.lastname: Joosten
authors.forename: Jos van der
authors.initials: Jv
authors.lastname: Meer
authors.forename: Mihai
authors.initials: M
authors.lastname: Netea
authors.forename: Marcel van
authors.initials: Mv
authors.lastname: Deuren
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000096:biosynthesis*; D054884:Host-Pathogen Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008050:Lipid A / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D016254:Mutagenesis, Insertional; D009345:Neisseria meningitidis / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014162:Transfection
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D008050:Lipid A; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C027315:lipid A-associated protein, Bacteria; D000217:Acyltransferases; C118473:LpxL protein, bacteria