Inhibition of Lipopolysaccharide-Induced Signal Transduction in Endotoxin-Tolerized Mouse Macrophages: Dysregulation of Cytokine, Chemokine, and Toll-Like Receptor 2 and 4 Gene Expression
| Autor: | Stefanie N. Vogel, Karen M. Kopydlowski, Andrei E. Medvedev |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Lipopolysaccharides
Chemokine MAP Kinase Signaling System medicine.medical_treatment Immunology Down-Regulation Receptors Cell Surface Biology Mice Immune Tolerance medicine Animals Drosophila Proteins Immunology and Allergy RNA Messenger Mice Inbred C3H Toll-like receptor Membrane Glycoproteins Tumor Necrosis Factor-alpha Monocyte Toll-Like Receptors NF-kappa B Molecular biology Toll-Like Receptor 2 Cell biology Mice Inbred C57BL Toll-Like Receptor 4 Transcription Factor AP-1 Cytokine medicine.anatomical_structure Gene Expression Regulation Chemokine secretion Macrophages Peritoneal TLR4 biology.protein Cytokines Tumor necrosis factor alpha Chemokines Signal transduction Interleukin-1 Signal Transduction |
| Zdroj: | The Journal of Immunology. 164:5564-5574 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.164.11.5564 |
| Popis: | In this study, the effect of in vitro endotoxin tolerance on LPS-induced mitogen-activated protein kinase activation, transcription factor induction, and cytokine, chemokine, and Toll-like receptor (TLR) 2 and 4 gene expression, as well as the involvement of TNF and IL-1 signaling pathways in tolerance, were examined. Pretreatment of mouse macrophages with LPS inhibited phosphorylation of the extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and p38 kinase; degradation of I-κBα (inhibitory protein that dissociates from NF-κB) and I-κBβ; and activation of the transcription factors NF-κB and AP-1 in response to subsequent LPS stimulation. These changes were accompanied by suppression of LPS-induced expression of mRNA for GM-CSF, IFN-γ-inducible protein-10, KC, JE/monocyte chemoattractant protein-1, macrophage-inflammatory protein-1β, and macrophage-inflammatory protein-2, with concurrent inhibition of chemokine secretion. In contrast to control cells, endotoxin-tolerant macrophages exhibited an increased basal level of TLR2 mRNA, and failed to increase levels of TLR2 mRNA or to down-regulate TLR4 gene expression upon restimulation with LPS. As judged by transcription factor activation, LPS and IL-1 were found to induce a state of cross-tolerance against each other, while no such reciprocal effect was seen for LPS and TNF-α. In addition, macrophages from TNFR I/II double knockout mice were LPS tolerizable, and blocking of endogenous TNF-α with TNFR-Fc fusion protein did not affect the capacity of LPS to tolerize macrophages. These data extend our understanding of LPS-signaling mechanisms that are inhibited in endotoxin-tolerized macrophages and suggest that endotoxin tolerance might result from impaired expression and/or functions of common signaling intermediates involved in LPS and IL-1 signaling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|