Abstract
Activation of interleukin-1 (IL-1) receptor (IL-1R), Toll-like receptor 2 (TLR2), and TLR4 triggers NF-kappaB and mitogen-activated protein kinase (MAPK)-dependent signaling, thereby initiating immune responses. Tollip has been implicated as a negative regulator of NF-kappaB signaling triggered by these receptors in in vitro studies. Here, deficient mice were used to determine the physiological contribution of Tollip to immunity. NF-kappaB, as well as MAPK, signaling appeared normal in Tollip-deficient cells stimulated with IL-1beta or the TLR4 ligand lipopolysaccharide (LPS). Similarly, IL-1beta- and TLR-driven activation of dendritic cells and lymphocytes was indistinguishable from wild-type cells. In contrast, the production of the proinflammatory cytokines, IL-6 and tumor necrosis factor alpha was significantly reduced after IL-1beta and LPS treatment at low doses but not at lethal doses of LPS. Tollip therefore controls the magnitude of inflammatory cytokine production in response to IL-1beta and LPS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Down-Regulation
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Interleukin-1 / pharmacology*
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Interleukin-1 Receptor-Associated Kinases
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / physiology*
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Lipopolysaccharides / pharmacology*
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Lymphocyte Activation / genetics
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Lymphocytes / drug effects
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Lymphocytes / immunology*
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Mice
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Mice, Mutant Strains
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Mitogen-Activated Protein Kinase Kinases / metabolism
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NF-kappa B / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Interleukin-1
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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NF-kappa B
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Tollip protein, mouse
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Tumor Necrosis Factor-alpha
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Interleukin-1 Receptor-Associated Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase Kinases