Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease

David A van Heel, Subrata Ghosh, Matt Butler, Karen A Hunt, Anna M C Lundberg, Tariq Ahmad, Dermot P B McGovern, Clive Onnie, Kenichi Negoro, Sue Goldthorpe, Brian M J Foxwell, Christopher G Mathew, Alastair Forbes, Derek P Jewell, Raymond J Playford

Research output: Contribution to journalArticlepeer-review

250 Citations (Scopus)

Abstract

Both NOD2 (CARD15) alleles are mutated in roughly 15% of patients with Crohn's disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFalpha or interleukin 1beta, but strong interleukin-8 secretion. MDP also substantially upregulated secretion of TNFalpha and interleukin 1beta induced by toll-like receptor ligands. These effects were abolished by the most common Crohn's NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn's disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NOD2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.
Original languageEnglish
Pages (from-to)1794-1796
Number of pages3
JournalLancet
Volume365
Issue number9473
DOIs
Publication statusPublished - 2005

Keywords

  • Acetylmuramyl-Alanyl-Isoglutamine
  • Crohn Disease
  • Genotype
  • Humans
  • Immunity, Innate
  • Interleukin-1
  • Interleukin-8
  • Intracellular Signaling Peptides and Proteins
  • Leukocytes, Mononuclear
  • Membrane Glycoproteins
  • Mutation
  • Nod2 Signaling Adaptor Protein
  • Receptor Cross-Talk
  • Receptors, Cell Surface
  • Signal Transduction
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Up-Regulation

Cite this