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Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide.

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.

Pubmed ID: 16428431

Authors

  • Didierlaurent A
  • Brissoni B
  • Velin D
  • Aebi N
  • Tardivel A
  • K√§slin E
  • Sirard JC
  • Angelov G
  • Tschopp J
  • Burns K

Journal

Molecular and cellular biology

Publication Data

February 23, 2006

Associated Grants

None

Mesh Terms

  • Animals
  • Dendritic Cells
  • Down-Regulation
  • Interleukin-1
  • Interleukin-1 Receptor-Associated Kinases
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Lymphocyte Activation
  • Lymphocytes
  • Mice
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinase Kinases
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha