title: Distinct pathways of lipopolysaccharide priming of human neutrophil respiratory burst: role of lipid mediator synthesis and sensitivity to interleukin-10.
abstract: OBJECTIVE
  Exposure of neutrophils to low doses of bacterial lipopolysaccharides enhances their readiness to respond with inflammatory mediator generation including oxygen radical formation to a subsequently applied inflammatory stimulus ("priming"). In the present study, we investigated the role of lipid mediator synthesis and the impact of the anti-inflammatory cytokine interleukin-10 on the lipopolysaccharide-dependent priming of human neutrophils in response to N-formyl-methionyl-leucyl-phenylalanine.
  
  
  METHODS
  Prospective, experimental study.
  
  
  METHODS
  Research laboratory at a university hospital.
  
  
  METHODS
  Isolated neutrophils from healthy volunteers.
  
  
  METHODS
  Incubation of isolated neutrophils with endotoxin.
  
  
  RESULTS
  Evidence for two distinct priming mechanisms was obtained. The first was strictly serum component dependent, proceeded via CD14, and was not inhibited by even high concentrations of interleukin-10. The second priming mechanism was serum component independent but nevertheless proceeded via CD14. It was linked with neutrophil synthesis of the platelet activating factor and resulted in the appearance of leukotrienes, in particular leukotriene B4, as far as exogenous arachidonic acid was provided. The employment of a platelet-activating factor receptor antagonist (WEB 2086) blocked leukotriene synthesis, and both WEB 2086 and a 5-lipoxygenase inhibitor (MK-886) suppressed the respiratory burst linked with this second priming pathway. This sequence of priming events was inhibited by interleukin-10, when this cytokine was coadministered with the priming agent lipopolysaccharide, whereas late interleukin-10 admixture was ineffective.
  
  
  CONCLUSIONS
  We conclude that two mechanisms of lipopolysaccharide priming of human neutrophil respiratory burst can be differentiated. One displays serum component dependence, is independent of neutrophil lipid mediator generation, and is not affected by interleukin-10. The other is serum independent although being operated via CD14, employs autocrine loops of platelet-activating factor and leukotriene B4 synthesis, and is sensitive to the inhibitory capacity of interleukin-10. These features may be relevant when the goal is to pharmacologically modify neutrophil functions in septic events.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Katja
authors.initials: K
authors.lastname: Hattar
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Angelika
authors.initials: A
authors.lastname: Schenkel
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D016718:Arachidonic Acid / Q000494:pharmacology; D019898:Autocrine Communication; D001381:Azepines / Q000494:pharmacology; D004926:Escherichia coli; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011446:Prospective Studies; D016897:Respiratory Burst / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D002722:Chlorobenzenes
chemical_list: D016718:Arachidonic Acid; D001381:Azepines; D007211:Indoles; D016753:Interleukin-10; D020024:Leukotriene Antagonists; D007975:Leukotriene B4; D015289:Leukotrienes; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010972:Platelet Activating Factor; D013481:Superoxides; D014230:Triazoles; C060893:MK-886; D002722:Chlorobenzenes; C052518:WEB 2086