期刊
JOURNAL OF IMMUNOLOGY
卷 164, 期 11, 页码 5564-5574出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.164.11.5564
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- PHS HHS [A1-18797] Funding Source: Medline
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-kappa B alpha (inhibitory protein that dissociates from NF-kappa B) and I-kappa B beta; and activation of the transcription factors NF-kappa B 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-gamma-inducible protein-10, KC, JE/monocyte chemoattractant protein-1, macrophage-inflammatory protein-1 beta, 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-alpha. In addition. macrophages from TNFR I/II double knockout mice were LPS tolerizable, and blocking of endogenous TNF-alpha 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-I signaling.
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