title: Endotoxin tolerance induces selective alterations in neutrophil function.
abstract: Endotoxin tolerance has the potential to limit phagocyte responses to Toll-like receptor (TLR) agonists, but the role of tolerance in regulating neutrophil responses is unknown. We investigated neutrophil responses to prolonged lipopolysaccharide (LPS) exposure and observed induction of tolerance in intracellular signaling pathways and respiratory burst. These effects were not prevented by granulocyte macrophage-colony stimulating factor (GM-CSF) pretreatment, and tolerized neutrophils retained the ability to respond to GM-CSF and other survival factors with a delay in apoptosis. In addition, LPS-exposed neutrophils showed continued generation of CXC chemokine ligand 8, which was not reduced in tolerized cells. Induction of tolerance was associated with a loss of TLR4 surface expression. Tolerance, therefore, induces a selective reprogramming of neutrophil function, but cells retain a predominantly proinflammatory phenotype.
authors.affiliation: Division of Genomic Medicine, University of Sheffield, M Floor, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK. l.c.parker@sheffield.ac.uk
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Parker
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Jones
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Prince
authors.forename: Steven K
authors.initials: SK
authors.lastname: Dower
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D019446:Endotoxemia / Q000276:immunology* / Q000503:physiopathology; D004731:Endotoxins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010641:Phenotype; D016897:Respiratory Burst / Q000187:drug effects / Q000276:immunology; D018805:Sepsis / Q000276:immunology* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000276:immunology
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases