Abstract
TLR2 plays a central role in the activation of innate immunity in response to Ft, the causative agent of tularemia. We reported previously that Ft LVS elicited strong, dose-dependent NF-kappaB reporter activity in TLR2-expressing human embryo kidney 293 T cells and that Ft LVS-induced murine macrophage proinflammatory cytokine gene and protein expression is TLR2-dependent. We demonstrated further that Ft can signal through TLR2 from within the phagosome and that phagosomal retention of Ft leads to greatly increased expression of a subset of proinflammatory genes. The two adaptor proteins associated with TLR2-mediated signaling are MyD88 and TIRAP. Although MyD88 is absolutely required for the Ft-induced macrophage cytokine response, the requirement for TIRAP can be overcome through retention of Ft within the phagosome. TIRAP-independent signaling was observed whether Ft was retained in the phagosome as a result of bacterial mutation (LVSDeltaiglC) or BFA-mediated inhibition of phagosome acidification. The requirement for TIRAP in TLR2 signaling could also be overcome by increasing the concentrations of synthetic bacterial TLR2 agonists. Taken together, these data suggest that prolonging or enhancing the interaction between TLR2 and its agonist overcomes the "bridging" function ascribed previously to TIRAP.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Cytokines / genetics
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Cytokines / immunology
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Francisella tularensis / genetics
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Francisella tularensis / immunology*
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Humans
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / microbiology
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / microbiology
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / immunology*
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Mice
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Mice, Knockout
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Mutation
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Myelin Proteins / genetics
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Myelin Proteins / immunology*
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology
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Phagosomes / genetics
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Phagosomes / immunology*
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Phagosomes / microbiology
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Proteolipids / genetics
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Proteolipids / immunology*
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / immunology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Toll-Like Receptor 2 / agonists
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology*
Substances
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Cytokines
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MAL protein, human
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Mal protein, mouse
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Membrane Glycoproteins
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Membrane Transport Proteins
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Myd88 protein, mouse
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Myelin Proteins
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Myelin and Lymphocyte-Associated Proteolipid Proteins
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Myeloid Differentiation Factor 88
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Proteolipids
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Receptors, Interleukin-1
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TIRAP protein, mouse
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Tlr2 protein, mouse
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Toll-Like Receptor 2