PMID:15220916

Citation	Watanabe, T, Kitani, A, Murray, PJ and Strober, W (2004) NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat. Immunol. 5:800-8
Abstract	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.
Links	PubMed Online version:10.1038/ni1092
Keywords	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
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