Crohn’s disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli
Version of Record online: 20 NOV 2007
© 2007 Blackwell Publishing Ltd
Volume 123, Issue 4, pages 600–605, April 2008
How to Cite
Kullberg, B. J., Ferwerda, G., De Jong, D. J., Drenth, J. P. H., Joosten, L. A. B., Van der Meer, J. W. M. and Netea, M. G. (2008), Crohn’s disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli. Immunology, 123: 600–605. doi: 10.1111/j.1365-2567.2007.02735.x
- Issue online: 9 JAN 2008
- Version of Record online: 20 NOV 2007
- Received 25 September 2006; revised 12 December 2006, 14 September 2007; accepted 14 September 2007.
- Crohn’s disease;
- Toll-like receptors;
- tumour necrosis factor
Mutations in nucleotide-binding oligomerization domain-2 (NOD2), leading to defective recognition of bacterial peptidoglycans, are associated with Crohn’s disease. The underlying mechanism that results in increased inflammation in the guts of the patients bearing NOD2 mutations is still unclear. We hypothesized that NOD2 engagement leads to cross-tolerance to stimulation of Toll-like receptors (TLR), and we investigated whether patients with Crohn’s disease who bear NOD2 mutations display a disturbed NOD2/TLR cross-tolerance. Peripheral blood mononuclear cells preincubated with NOD2 ligands were specifically down-regulated for the production of tumour necrosis factor-α (TNF-α) induced by the TLR4 ligand lipopolysaccharide, as well as by intestinal microorganisms, whereas the production of anti-inflammatory cytokines was not modulated. While in cells isolated from patients with Crohn’s disease with the wild-type NOD2 allele, the NOD2 engagement led to a similar cross-tolerance to TLR4-dependent stimulation of TNF-α, the cross-tolerance between NOD2 and TLR4 was absent in the cells of five patients homozygous for the 3020insC NOD2 mutation, leading to uninhibited release of TNF-α by TLR4 ligands and intestinal bacteria. In conclusion, we propose the absence of NOD2/TLR4 cross-tolerance as a central mechanism for the increased susceptibility to Crohn’s disease in individuals with NOD2 mutations.