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dc.contributor.authorWang, Jiang Huai
dc.contributor.authorDoyle, Majella
dc.contributor.authorManning, Brian J
dc.contributor.authorDi Wu, Qiong
dc.contributor.authorBlankson, Siobhan
dc.contributor.authorRedmond, H Paul
dc.date.accessioned2012-02-03T15:10:27Z
dc.date.available2012-02-03T15:10:27Z
dc.date.issued2012-02-03T15:10:27Z
dc.identifier.citationJ Biol Chem. 2002 Sep 27;277(39):36068-75. Epub 2002 Jul 19.en_GB
dc.identifier.issn0021-9258 (Print)en_GB
dc.identifier.issn0021-9258 (Linking)en_GB
dc.identifier.pmid12133836en_GB
dc.identifier.doi10.1074/jbc.M205584200en_GB
dc.identifier.urihttp://hdl.handle.net/10147/209033
dc.description.abstractTolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-alpha and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membrane-bound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPS-tolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-alpha and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLP-induced TLR2 overexpression. These results demonstrate that BLP tolerance develops through down-regulation of TLR2 expression.
dc.language.isoengen_GB
dc.subject.meshAntigens, CD14/biosynthesis/metabolismen_GB
dc.subject.meshBacterial Outer Membrane Proteins/*pharmacologyen_GB
dc.subject.meshBlotting, Westernen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshCell Nucleus/metabolismen_GB
dc.subject.meshCell Separationen_GB
dc.subject.meshCulture Media, Serum-Free/pharmacologyen_GB
dc.subject.meshCytokines/metabolismen_GB
dc.subject.meshDown-Regulationen_GB
dc.subject.mesh*Drosophila Proteinsen_GB
dc.subject.meshFlow Cytometryen_GB
dc.subject.meshHumansen_GB
dc.subject.mesh*Immune Toleranceen_GB
dc.subject.meshInterleukin-6/metabolismen_GB
dc.subject.meshLipopolysaccharides/metabolism/*pharmacologyen_GB
dc.subject.meshLipoproteins/*metabolismen_GB
dc.subject.meshLuciferases/metabolismen_GB
dc.subject.meshMAP Kinase Signaling Systemen_GB
dc.subject.meshMembrane Glycoproteins/*biosynthesis/metabolismen_GB
dc.subject.meshMicroscopy, Fluorescenceen_GB
dc.subject.meshMonocytes/immunology/metabolismen_GB
dc.subject.meshNF-kappa B/metabolismen_GB
dc.subject.meshPhosphorylationen_GB
dc.subject.meshReceptors, Cell Surface/*biosynthesis/metabolismen_GB
dc.subject.meshToll-Like Receptor 2en_GB
dc.subject.meshToll-Like Receptor 4en_GB
dc.subject.meshToll-Like Receptorsen_GB
dc.subject.meshTransfectionen_GB
dc.subject.meshTumor Necrosis Factor-alpha/metabolismen_GB
dc.titleInduction of bacterial lipoprotein tolerance is associated with suppression of toll-like receptor 2 expression.en_GB
dc.contributor.departmentDepartment of Academic Surgery, National University of Ireland, Cork University, Hospital, Cork, Ireland. jh.wang@ucc.ieen_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
dc.description.provinceMunster
html.description.abstractTolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-alpha and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membrane-bound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPS-tolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-alpha and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLP-induced TLR2 overexpression. These results demonstrate that BLP tolerance develops through down-regulation of TLR2 expression.


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