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Bacterial lipoprotein‐induced tolerance is reversed by overexpression of IRAK‐1
Author(s) -
Li Chong Hui,
Liu Jinghua,
An Mingbang,
Redmond H Paul,
Wang Jiang Huai
Publication year - 2012
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2011.37
Subject(s) - tlr2 , transactivation , transfection , tumor necrosis factor alpha , cytokine , biology , signal transduction , tlr4 , microbiology and biotechnology , immunology , cell culture , transcription factor , gene , biochemistry , genetics
Tolerance to bacterial cell wall components including bacterial lipoprotein (BLP) represents an essential regulatory mechanism during bacterial infection. Reduced Toll‐like receptor 2 (TLR2) and IL‐1 receptor‐associated kinase 1 (IRAK‐1) expression is a characteristic of the downregulated TLR signaling pathway observed in BLP‐tolerised cells. In this study, we attempted to clarify whether TLR2 and/or IRAK‐1 are the key molecules responsible for BLP‐induced tolerance. Transfection of HEK293 cells and THP‐1 cells with the plasmid encoding TLR2 affected neither BLP tolerisation‐induced NF‐κB deactivation nor BLP tolerisation‐attenuated pro‐inflammatory cytokine tumor necrosis factor alpha (TNF‐α) production, indicating that BLP tolerance develops despite overexpression of TLR2 in these cells. In contrast, overexpression of IRAK‐1 reversed BLP‐induced tolerance, as transfection of IRAK‐1 expressing vector resulted in a dose‐dependent NF‐κB activation and TNF‐α release in BLP‐tolerised cells. Furthermore, BLP‐tolerised cells exhibited markedly repressed NF‐κB p65 phosphorylation and impaired binding of p65 to several pro‐inflammatory cytokine gene promoters including TNF‐α and interleukin‐6 (IL‐6). Overexpression of IRAK‐1 restored the nuclear transactivation of p65 at both TNF‐α and IL‐6 promoters. These results indicate a crucial role for IRAK‐1 in BLP‐induced tolerance, and suggest IRAK‐1 as a potential target for manipulation of the TLR‐mediated inflammatory response during microbial sepsis.