NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses

Nat Immunol. 2004 Aug;5(8):800-8. doi: 10.1038/ni1092. Epub 2004 Jun 27.


The mechanism by which mutations in CARD15, which encodes nucleotide-binding oligomerization domain 2 (NOD2), cause Crohn disease is poorly understood. Because signaling via mutated NOD2 proteins leads to defective activation of the transcription factor NF-kappa B, one proposal is that mutations cause deficient NF-kappa B-dependent T helper type 1 (T(H)1) responses and increased susceptibility to infection. However, this idea is inconsistent with the increased T(H)1 responses characteristic of Crohn disease. Here we used Card15(-/-) mice to show that intact NOD2 signaling inhibited Toll-like receptor 2-driven activation of NF-kappa B, particularly of the NF-kappa B subunit c-Rel. Moreover, NOD2 deficiency or the presence of a Crohn disease-like Card15 mutation increased Toll-like receptor 2-mediated activation of NF-kappa B-c-Rel, and T(H)1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive T(H)1 responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Crohn Disease / genetics
  • Crohn Disease / metabolism
  • Flow Cytometry
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mutation
  • NF-kappa B / metabolism
  • Nod2 Signaling Adaptor Protein
  • Receptors, Cell Surface / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / immunology*
  • Th1 Cells / immunology*
  • Toll-Like Receptor 2
  • Toll-Like Receptors


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Receptors, Cell Surface
  • Toll-Like Receptor 2
  • Toll-Like Receptors