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Journal of Crohn's and Colitis: 9 (10)


Laurence J. Egan, Ireland

Associate Editors

Maria T. Abreu, USAShomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKGijs van den Brink, NLSéverine Vermeire, Belgium


Published on behalf of

NOD2 activity modulates the phenotype of LPS-stimulated dendritic cells to promote the development of T-helper type 2-like lymphocytes — Possible implications for NOD2-associated Crohn's disease

Matt Butler, Rakesh Chaudhary, David A. van Heel, Raymond J. Playford, Subrata Ghosh
DOI: http://dx.doi.org/10.1016/j.crohns.2007.08.006 106-115 First published online: 1 December 2007


Sensing of commensal microorganisms via Toll-like receptors (TLR) in the gut is essential for maintaining intestinal homeostasis in healthy individuals. Conversely, Crohn's disease is characterised by an inappropriate T helper-type 1 (Th1)-mediated immune response towards these same microorganisms. NOD2 is expressed by dendritic cells (DC) and mediates responses to bacterial muramyl-dipeptides (MDP). Mutations in NOD2 (CARD15) have recently been associated with susceptibility to Crohn's disease although the underlying mechanisms have yet to be established. We investigated the functional outcome of NOD2 and TLR4-mediated activation in monocyte-derived DC from wild-type NOD2 healthy controls and NOD2 frame-shift mutation-carrying Crohn's disease patients. In wild-type DC, MDP acted synergistically with LPS to amplify inflammatory cytokine production, enhance co-stimulatory molecule expression, and produce DC that promoted the proliferation of naïve, allogeneic, CD4+ T lymphocytes with a Th2-like cytokine profile. By contrast, DC carrying homozygous NOD2 mutations were unable to react to MDP, responded to LPS only, and promoted the development of Th1 cells. These results suggest activation of the NOD2 pathway in DC modulates their response to TLR agonists and regulates their ability to induce polarised Th1 responses. As a consequence, Crohn's disease patients with defective NOD2 may be predisposed to the generation of strongly polarised Th1 responses against common commensal microorganisms.

  • Abbreviations
    caspase recruitment domain 15
    dendritic cell
    muramyl dipeptide
    nucleotide oligomerization domain-2
    peripheral blood mononuclear cell
    pattern recognition receptor
    T helper-type 1/2
    Toll-like receptor.
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