Abstract
Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity and disease resistance. The adaptor protein Tollip was identified initially as an intermediate in interleukin (IL)-1 signaling. Here we report that Tollip also associates directly with TLR2 and TLR4 and plays an inhibitory role in TLR-mediated cell activation. Inhibition by Tollip is mediated through its ability to potently suppress the activity of IL-1 receptor-associated kinase (IRAK) after TLR activation. In addition, we show for the first time that Tollip is a bona fide substrate for IRAK and is phosphorylated by IRAK upon stimulation with lipopolysaccharide or IL-1. Negative regulation of TLR signaling by Tollip may therefore serve to limit the production of proinflammatory mediators during inflammation and infection.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Carrier Proteins / metabolism*
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Cell Line
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Dose-Response Relationship, Drug
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Drosophila Proteins*
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Escherichia coli / metabolism
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Humans
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Immunoblotting
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Interleukin-1 / metabolism
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Interleukin-1 Receptor-Associated Kinases
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Intracellular Signaling Peptides and Proteins*
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Lipopolysaccharides / metabolism
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Membrane Glycoproteins / metabolism*
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Protein Binding
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Protein Kinases / metabolism
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Protein Structure, Tertiary
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Receptors, Cell Surface / metabolism*
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Signal Transduction*
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Time Factors
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
Substances
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Carrier Proteins
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Drosophila Proteins
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Interleukin-1
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Membrane Glycoproteins
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Receptors, Cell Surface
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TLR2 protein, human
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TLR4 protein, human
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TOLLIP protein, human
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptors
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Protein Kinases
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Interleukin-1 Receptor-Associated Kinases