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Negative regulation of toll-like receptor-mediated signaling by Tollip.

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.

Pubmed ID: 11751856


  • Zhang G
  • Ghosh S


The Journal of biological chemistry

Publication Data

March 1, 2002

Associated Grants

  • Agency: NIAID NIH HHS, Id: R37 AI 33443
  • Agency: NIAID NIH HHS, Id: R37 AI033443

Mesh Terms

  • Carrier Proteins
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drosophila Proteins
  • Escherichia coli
  • Humans
  • Immunoblotting
  • Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Phosphorylation
  • Plasmids
  • Precipitin Tests
  • Protein Binding
  • Protein Kinases
  • Protein Structure, Tertiary
  • Receptors, Cell Surface
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors