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Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing.

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.

Pubmed ID: 15692052

Authors

  • Maeda S
  • Hsu LC
  • Liu H
  • Bankston LA
  • Iimura M
  • Kagnoff MF
  • Eckmann L
  • Karin M

Journal

Science (New York, N.Y.)

Publication Data

February 4, 2005

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI43477
  • Agency: NIAID NIH HHS, Id: AI56075
  • Agency: NIDDK NIH HHS, Id: DK07202
  • Agency: NIDDK NIH HHS, Id: DK35108

Mesh Terms

  • Acetylmuramyl-Alanyl-Isoglutamine
  • Animals
  • Anti-Bacterial Agents
  • Apoptosis
  • Bacteria
  • Cells, Cultured
  • Colitis
  • Colon
  • Crohn Disease
  • Cytokines
  • Dextran Sulfate
  • Interleukin-1
  • Intestinal Mucosa
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Macrophage Activation
  • Macrophages
  • Mice
  • Mutation
  • NF-kappa B
  • Nod2 Signaling Adaptor Protein
  • Peptidoglycan
  • Signal Transduction