TAK1 contributes to the enhanced responsiveness of LTB(4)-treated neutrophils to Toll-like receptor ligands
| Autor: | Carine Paquet-Bouchard, Stéphanie Fiola, Jean Gosselin, Eric Gaudreault, Manon Le Bel, Patricia Lacerte, Marina Tiemi Shio, Martin Olivier |
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| Rok vydání: | 2012 |
| Předmět: |
Lipopolysaccharides
Leukotriene B4 Neutrophils Immunology Blotting Western Biology Ligands p38 Mitogen-Activated Protein Kinases Proinflammatory cytokine chemistry.chemical_compound Immunology and Allergy Humans Receptor Protein Kinase Inhibitors Cells Cultured Toll-like receptor Dose-Response Relationship Drug Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Interleukin-8 Drug Synergism General Medicine Flow Cytometry MAP Kinase Kinase Kinases Toll-Like Receptor 2 Cell biology Teichoic Acids Toll-Like Receptor 4 TLR2 HEK293 Cells Interleukin-1 Receptor-Associated Kinases chemistry Oligodeoxyribonucleotides Toll-Like Receptor 9 TLR4 Tumor necrosis factor alpha RNA Interference Signal transduction |
| Zdroj: | International immunology. 24(11) |
| ISSN: | 1460-2377 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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