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

doi:10.1016/S0140-6736(05)66582-8

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

Lancet. 2005 May;365(9473):1794-6. doi: 10.1016/S0140-6736(05)66582-8.

Authors

David A van Heel¹, 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

Affiliation

¹ Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London, UK. d.vanheel@imperial.ac.uk

PMID: 15910952
DOI: 10.1016/S0140-6736(05)66582-8

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylmuramyl-Alanyl-Isoglutamine / metabolism
Acetylmuramyl-Alanyl-Isoglutamine / pharmacology*
Crohn Disease / genetics
Crohn Disease / immunology*
Crohn Disease / metabolism
Genotype
Humans
Immunity, Innate
In Vitro Techniques
Interleukin-1 / biosynthesis
Interleukin-1 / metabolism
Interleukin-8 / biosynthesis
Interleukin-8 / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Leukocytes, Mononuclear / metabolism
Membrane Glycoproteins / metabolism*
Mutation
Nod2 Signaling Adaptor Protein
Receptor Cross-Talk
Receptors, Cell Surface / metabolism*
Signal Transduction*
Toll-Like Receptors
Tumor Necrosis Factor-alpha / biosynthesis
Tumor Necrosis Factor-alpha / metabolism
Up-Regulation

Substances

Interleukin-1
Interleukin-8
Intracellular Signaling Peptides and Proteins
Membrane Glycoproteins
NOD2 protein, human
Nod2 Signaling Adaptor Protein
Receptors, Cell Surface
Toll-Like Receptors
Tumor Necrosis Factor-alpha
Acetylmuramyl-Alanyl-Isoglutamine