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NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease

Mihai G Netea1, Bart Jan Kullberg, Dirk J de Jong

  • 1Department of Medicine, University Medical Center St Radboud, Nijmegen, The Netherlands. M.Netea@aig.umcn.nl

European Journal of Immunology
|June 24, 2004
PubMed

Insights

Mutations in the NOD2 gene impair the release of anti-inflammatory cytokine IL-10. This defective NOD2 function may contribute to Crohn's disease inflammation.

Area of Science:

  • Immunology
  • Genetics
  • Gastroenterology

Background:

  • NOD2 gene mutations are linked to increased Crohn's disease susceptibility.
  • The precise mechanisms by which NOD2 influences Crohn's disease pathogenesis are not fully understood.

Purpose of the Study:

  • To investigate the functional consequences of a specific NOD2 mutation (3020insC) on cytokine release.
  • To explore the role of defective NOD2 function in Crohn's disease pathophysiology.

Main Methods:

  • Assessed IL-10 release from blood mononuclear cells stimulated with Toll-like receptor (TLR) ligands.
  • Compared cytokine release in individuals with the NOD2 3020insC mutation versus controls.
  • Stimulated cells with bacterial components (peptidoglycan, Pam3Cys-KKKK, LPS) and enteric bacteria (Bacteroides species).

Main Results:

  • The NOD2 3020insC mutation caused defective IL-10 release upon stimulation with TLR2 ligands (peptidoglycan, Pam3Cys-KKKK), but not TLR4 ligand (LPS).
  • Cells from Crohn's disease patients homozygous for the NOD2 mutation showed reduced anti-inflammatory cytokine release when exposed to Bacteroides species.
  • Defective NOD2 function leads to a pro-inflammatory cytokine bias.

Conclusions:

  • Defective NOD2 function, particularly the 3020insC mutation, impairs anti-inflammatory responses to specific bacterial stimuli.
  • This impaired response may contribute to the excessive inflammation characteristic of Crohn's disease.

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