Bacterial lipoprotein-induced tolerance is reversed by overexpression of IRAK-1.
dc.contributor.author | Li, Chong Hui | |
dc.contributor.author | Liu, Jinghua | |
dc.contributor.author | An, Mingbang | |
dc.contributor.author | Redmond, H Paul | |
dc.contributor.author | Wang, Jiang Huai | |
dc.date.accessioned | 2012-08-20T14:59:08Z | |
dc.date.available | 2012-08-20T14:59:08Z | |
dc.date.issued | 2012-03 | |
dc.identifier.citation | Bacterial lipoprotein-induced tolerance is reversed by overexpression of IRAK-1. 2012, 90 (3):314-20 Immunol. Cell Biol. | en_GB |
dc.identifier.issn | 1440-1711 | |
dc.identifier.pmid | 21537341 | |
dc.identifier.doi | 10.1038/icb.2011.37 | |
dc.identifier.uri | http://hdl.handle.net/10147/239195 | |
dc.description.abstract | 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. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Immunology and cell biology | en_GB |
dc.subject.mesh | Bacterial Proteins | |
dc.subject.mesh | Cell Line | |
dc.subject.mesh | Gene Expression Regulation | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Immune Tolerance | |
dc.subject.mesh | Inflammation Mediators | |
dc.subject.mesh | Interleukin-1 Receptor-Associated Kinases | |
dc.subject.mesh | Interleukin-6 | |
dc.subject.mesh | Lipoproteins | |
dc.subject.mesh | NF-kappa B | |
dc.subject.mesh | Phosphorylation | |
dc.subject.mesh | Sepsis | |
dc.subject.mesh | Signal Transduction | |
dc.subject.mesh | Toll-Like Receptor 2 | |
dc.subject.mesh | Transcriptional Activation | |
dc.subject.mesh | Transgenes | |
dc.subject.mesh | Tumor Necrosis Factor-alpha | |
dc.title | Bacterial lipoprotein-induced tolerance is reversed by overexpression of IRAK-1. | en_GB |
dc.type | Article | en |
dc.contributor.department | Department of Academic Surgery, University College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital, Cork, Ireland. | en_GB |
dc.identifier.journal | Immunology and cell biology | en_GB |
dc.description.province | Munster | en |
html.description.abstract | 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. |