title: TAK1 contributes to the enhanced responsiveness of LTB(4)-treated neutrophils to Toll-like receptor ligands.
abstract: Pattern-recognition receptors such as Toll-like receptors (TLRs) are essential sensors implicated in the early and efficient innate immune response against pathogens. We have previously demonstrated that leukotriene B(4)(LTB(4)) has the capacity to enhance leukocyte responses to TLR9 ligands and to control viral infection. In this report, we provide evidence that LTB(4) treatment of human neutrophils leads to a potentiation in proinflammatory cytokine secretion induced by various myeloid differentiation factor 88-dependent TLR agonists. LTB(4) failed to enhance TLR mRNA levels as well as expression of TLR2 and TLR4 receptors, suggesting that LTB(4) acts through intracellular mechanism(s) to potentiate neutrophil responses to TLR ligands. We found that while IRAK can be activated by LTB(4), this process is dispensable to LTB(4) to potentiate neutrophil responses to TLR ligands since pretreatment of neutrophils with IRAK1/4 inhibitor did not affect its potentiating effects. However, our data clearly show that LTB(4) treatment of neutrophils led to the phosphorylation of downstream signaling molecules, TAK1 and p38, a process found essential to observe an increased secretion of cytokines by neutrophils activated with TLR ligands. Pretreatment of neutrophils with TAK1 or p38 kinase inhibitors strongly repressed the effect of LTB(4) on cytokine synthesis by neutrophils stimulated with LTA, LPS or CpG. The same pattern was observed in agonist-treated human embryonic kidney 293 cells transfected with TAK1-targeting siRNA where secretion of IL-8 was significantly reduced to basal levels. These results indicate that TAK1 and p38 kinases appear to be central in the 'priming effect' of LTB(4) on neutrophils to enhance response to TLR ligands.
authors: Laboratory of Innate Immunology, Centre Hospitalier Universitaire de Quebec Research Center (Centre Hospitalier de l'Université Laval) and Department of Molecular Medicine, Laval University Quebec G1V 4G2, Canada.
authors: Éric
authors: É
authors: Gaudreault
authors: Carine
authors: C
authors: Paquet-Bouchard
authors: Stéphanie
authors: S
authors: Fiola
authors: Manon
authors: M
authors: Le Bel
authors: Patricia
authors: P
authors: Lacerte
authors: Marina Tiemi
authors: MT
authors: Shio
authors: Martin
authors: M
authors: Olivier
authors: Jean
authors: J
authors: Gosselin
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D007975:Leukotriene B4 / Q000276:immunology* / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000276:immunology / Q000494:pharmacology; D034622:RNA Interference / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; D016209:Interleukin-8; D007975:Leukotriene B4; D008024:Ligands; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D009838:Oligodeoxyribonucleotides; D047428:Protein Kinase Inhibitors; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C526902:CpG ODN 2216; C009900:lipoteichoic acid; C507768:IRAK1 protein, human