Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease.
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.
van Heel
David A
DA
Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London, UK. d.vanheel@imperial.ac.uk
Ghosh
Subrata
S
Butler
Matt
M
Hunt
Karen A
KA
Lundberg
Anna M C
AM
Ahmad
Tariq
T
McGovern
Dermot P B
DP
Onnie
Clive
C
Negoro
Kenichi
K
Goldthorpe
Sue
S
Foxwell
Brian M J
BM
Mathew
Christopher G
CG
Forbes
Alastair
A
Jewell
Derek P
DP
Playford
Raymond J
RJ
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism / Q000494:pharmacology*; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D020239:Receptor Cross-Talk; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation
D007375:Interleukin-1; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine