Peer-Reviewed Journal Details
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Li, CH,Liu, JH,An, MB,Redmond, HP,Wang, JH
Immunology And Cell Biology
Bacterial lipoprotein-induced tolerance is reversed by overexpression of IRAK-1
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IL-1 receptor-associated kinase 1 Toll-like receptor 2 NF-kappa B chromatin immunoprecipitation monocytes/macrophages tolerance NF-KAPPA-B TOLL-LIKE RECEPTORS ENDOTOXIN TOLERANCE INNATE IMMUNITY CROSS-TOLERANCE ACTIVATION EXPRESSION SEPSIS LIPOPOLYSACCHARIDE MACROPHAGES
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-kappa B deactivation nor BLP tolerisation-attenuated pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) 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-kappa B activation and TNF-alpha release in BLP-tolerised cells. Furthermore, BLP-tolerised cells exhibited markedly repressed NF-kappa B p65 phosphorylation and impaired binding of p65 to several pro-inflammatory cytokine gene promoters including TNF-alpha and interleukin-6 (IL-6). Overexpression of IRAK-1 restored the nuclear transactivation of p65 at both TNF-alpha 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. Immunology and Cell Biology (2012) 90, 314-320; doi:10.1038/icb.2011.37; published online 3 May 2011
DOI 10.1038/icb.2011.37
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