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The effect of NOD2 activation on TLR2-mediated cytokine responses is dependent on activation dose and NOD2 genotype

Genes & Immunity volume 9, pages 274–278 (2008)Cite this article

Abstract

The mechanism by which mutations in NOD2 predispose to Crohn's disease (CD) is incompletely understood. In mice, NOD2 has been found to function as a negative regulator of Toll-like receptor 2 (TLR2) signaling. In contrast, studies in humans so far showed no negative regulatory interaction between NOD2 and TLR2, and in fact suggest a synergistic effect between the two. Here, we show that this interaction is dose dependent. Adding low doses of muramyl dipeptide (MDP) to TLR2 primed monocytes results in a significant increase in cytokine production, whereas adding higher doses of MDP led to a striking downregulation of the responses. This downregulation by high-dose MDP does not occur in monocytes from NOD2-deficient patients. The inhibitory role of NOD2 at high concentrations of MDP implicates a safety mechanism to prevent exaggerated antibacterial immune responses in the gut to high or perpetuating bacterial load. This regulatory mechanism is lost in NOD2-deficient CD patients.

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    M E A Borm, G Kraal & G Bouma

  2. Department of Gastroenterology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    A A van Bodegraven, C J J Mulder & G Bouma

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  1. M E A Borm
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  2. A A van Bodegraven
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  3. C J J Mulder
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  4. G Kraal
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  5. G Bouma
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Correspondence to G Bouma.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Borm, M., van Bodegraven, A., Mulder, C. et al. The effect of NOD2 activation on TLR2-mediated cytokine responses is dependent on activation dose and NOD2 genotype. Genes Immun 9, 274–278 (2008). https://doi.org/10.1038/gene.2008.9

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