Bacterial lipoprotein-induced self-tolerance and cross-tolerance to LPS are associated with reduced IRAK-1 expression and MyD88-IRAK complex formation.
AffiliationDepartment of Academic Surgery, National University of Ireland (NUI)/University, College Cork, Cork University Hospital, Cork, Ireland.
MeSHAdaptor Proteins, Signal Transducing/biosynthesis/*drug effects
Immune Tolerance/*drug effects/immunology
Interleukin-1 Receptor-Associated Kinases
Intracellular Signaling Peptides and Proteins/*drug effects
Lipopolysaccharides/*antagonists & inhibitors/pharmacology
Myeloid Differentiation Factor 88
Neoplasm Proteins/biosynthesis/drug effects
Protein-Serine-Threonine Kinases/biosynthesis/*drug effects
RNA, Messenger/biosynthesis/drug effects
Signal Transduction/drug effects/immunology
Toll-Like Receptor 2/biosynthesis/drug effects
Toll-Like Receptor 4/biosynthesis/drug effects
Tumor Necrosis Factor-alpha/biosynthesis/drug effects
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CitationJ Leukoc Biol. 2006 Apr;79(4):867-75. Epub 2006 Feb 3.
JournalJournal of leukocyte biology
AbstractTolerance to bacterial cell-wall components may represent an essential regulatory mechanism during bacterial infection. We have demonstrated previously that the inhibition of nuclear factor (NF)-kappaB and mitogen-activated protein kinase activation was present in bacterial lipoprotein (BLP) self-tolerance and its cross-tolerance to lipopolysaccharide (LPS). In this study, the effect of BLP-induced tolerance on the myeloid differentiation factor 88 (MyD88)-dependent upstream signaling pathway for NF-kappaB activation in vitro was examined further. When compared with nontolerant human monocytic THP-1 cells, BLP-tolerant cells had a significant reduction in tumor necrosis factor alpha (TNF-alpha) production in response to a high-dose BLP (86+/-12 vs. 6042+/-245 ng/ml, P < 0.01) or LPS (341+/-36 vs. 7882+/-318 ng/ml, P < 0.01) stimulation. The expression of Toll-like receptor 2 (TLR2) protein was down-regulated in BLP-tolerant cells, whereas no significant differences in TLR4, MyD88, interleukin-1 receptor-associated kinase 4 (IRAK-4), and TNF receptor-associated factor 6 expression were observed between nontolerant and BLP-tolerant cells, as confirmed by Western blot analysis. The IRAK-1 protein was reduced markedly in BLP-tolerant cells, although IRAK-1 mRNA expression remained unchanged as revealed by real-time reverse transcriptase-polymerase chain reaction analysis. Furthermore, decreased MyD88-IRAK immunocomplex formation, as demonstrated by immunoprecipitation, was observed in BLP-tolerant cells following a second BLP or LPS stimulation. BLP pretreatment also resulted in a marked inhibition in total and phosphorylated inhibitor of kappaB-alpha (IkappaB-alpha) expression, which was not up-regulated by subsequent BLP or LPS stimulation. These results demonstrate that in addition to the down-regulation of TLR2 expression, BLP tolerance is associated with a reduction in IRAK-1 expression, MyD88-IRAK association, and IkappaB-alpha phosphorylation. These findings further elucidate the molecular mechanisms underlying bacterial peptide tolerance.
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