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Bacterial lipoprotein‐induced self‐tolerance and cross‐tolerance to LPS are associated with reduced IRAK‐1 expression and MyD88‐IRAK complex formation
Author(s) -
Li Chong Hui,
Wang Jiang Huai,
Redmond H. Paul
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0905505
Subject(s) - biology , tlr4 , tlr2 , lipopolysaccharide , tumor necrosis factor alpha , western blot , microbiology and biotechnology , receptor , toll like receptor , signal transduction , kinase , immunology , innate immune system , biochemistry , gene
Tolerance 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)‐κB 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‐κB 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 α (TNF‐α) 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 κB‐α (IκB‐α) 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 IκB‐α phosphorylation. These findings further elucidate the molecular mechanisms underlying bacterial peptide tolerance.