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

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 journal › Article › peer-review

273 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 language	English
Pages (from-to)	1794-1796
Number of pages	3
Journal	Lancet
Volume	365
Issue number	9473
DOIs	https://doi.org/10.1016/S0140-6736(05)66582-8
Publication status	Published - 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

Access to Document

10.1016/S0140-6736(05)66582-8

Cite this

van Heel, D. A., Ghosh, S., Butler, M., Hunt, K. A., Lundberg, A. M. C., Ahmad, T., McGovern, D. P. B., Onnie, C., Negoro, K., Goldthorpe, S., Foxwell, B. M. J., Mathew, C. G., Forbes, A., Jewell, D. P., & Playford, R. J. (2005). Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet, 365(9473), 1794-1796. https://doi.org/10.1016/S0140-6736(05)66582-8

@article{588715f78bea4d2595e9870fe99f0f96,

title = "Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease",

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.",

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",

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

year = "2005",

doi = "10.1016/S0140-6736(05)66582-8",

language = "English",

volume = "365",

pages = "1794--1796",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier",

number = "9473",

}

TY - JOUR

T1 - Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease

AU - van Heel, David A

AU - Ghosh, Subrata

AU - Butler, Matt

AU - Hunt, Karen A

AU - Lundberg, Anna M C

AU - Ahmad, Tariq

AU - McGovern, Dermot P B

AU - Onnie, Clive

AU - Negoro, Kenichi

AU - Goldthorpe, Sue

AU - Foxwell, Brian M J

AU - Mathew, Christopher G

AU - Forbes, Alastair

AU - Jewell, Derek P

AU - Playford, Raymond J

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

KW - Acetylmuramyl-Alanyl-Isoglutamine

KW - Crohn Disease

KW - Genotype

KW - Humans

KW - Immunity, Innate

KW - Interleukin-1

KW - Interleukin-8

KW - Intracellular Signaling Peptides and Proteins

KW - Leukocytes, Mononuclear

KW - Membrane Glycoproteins

KW - Mutation

KW - Nod2 Signaling Adaptor Protein

KW - Receptor Cross-Talk

KW - Receptors, Cell Surface

KW - Signal Transduction

KW - Toll-Like Receptors

KW - Tumor Necrosis Factor-alpha

KW - Up-Regulation

U2 - 10.1016/S0140-6736(05)66582-8

DO - 10.1016/S0140-6736(05)66582-8

M3 - Article

C2 - 15910952

VL - 365

SP - 1794

EP - 1796

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9473

ER -