NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype

Neth J Med. 2005 Sep;63(8):305-8.


Background: Mutations of the NOD2 gene increase the susceptibility of humans to Crohn's disease. NOD2 is a cytoplasmic receptor for the bacterial product peptidoglycan. There is considerable controversy in the literature whether the most common mutation in Crohn's disease, the 3020insC NOD2, leads to a loss of function, i.e. decreased cytokine production, or to the reverse, i.e. a gain of function. In previous papers we proposed the former, since we could show decreased cytokine production with a net proinflammatory status after exposure to muramyl dipeptide (MDP).

Methods: Because of recent data in the literature showing increased interleukin-beta (IL-1beta) production in mice with the corresponding NOD2 mutation, we investigated the production of this cytokine by cells of patients with Crohn's disease, either homozygous or heterozygous for the 3020insC mutation, and compared it with that of patients with Crohn's disease bearing the wild-type allele.

Results: A strongly decreased production of IL-1beta by peripheral mononuclear cells was found upon exposure to either peptidoglycan or peptidoglycan-derived MDP in homozygous patients bearing the 3020insC NOD2mutation.

Conclusion: This sustains the hypothesis that the 3020insC mutation in the human NOD2 gene leads to a loss-of-function phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / administration & dosage
  • Acetylmuramyl-Alanyl-Isoglutamine / metabolism
  • Alleles
  • Case-Control Studies
  • Crohn Disease / genetics*
  • Crohn Disease / immunology
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease
  • Homozygote
  • Humans
  • Interleukin-1 / biosynthesis
  • Interleukin-1 / blood*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / immunology
  • Leukocytes, Mononuclear / immunology*
  • Lipopeptides
  • Mutation
  • Nod2 Signaling Adaptor Protein
  • Oligopeptides / administration & dosage
  • Oligopeptides / metabolism
  • Peptidoglycan / administration & dosage
  • Peptidoglycan / metabolism
  • Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Toll-Like Receptor 2 / genetics*
  • Toll-Like Receptor 2 / immunology


  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • Lipopeptides
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Oligopeptides
  • Peptidoglycan
  • Toll-Like Receptor 2
  • Acetylmuramyl-Alanyl-Isoglutamine
  • macrophage stimulatory lipopeptide 2