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-κB, one proposal is that mutations cause deficient NF-κB-dependent T helper type 1 (TH1) responses and increased susceptibility to infection. However, this idea is inconsistent with the increased TH1 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-κB, particularly of the NF-κB 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-κB–c-Rel, and TH1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive TH1 responses.
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We thank J.T. Rosenbaum and M.P. Davey (Casey Eye Institute, Oregon Health and Science University) for providing us with the plasmid expressing mouse Card15; and C. Ma and S. Fichtner (Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases) for comments and technical assistance. Supported in part by the Cancer Center CORE (P30 CA21765) and the American Lebanese Associated Charities.
The authors declare no competing financial interests.
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Watanabe, T., Kitani, A., Murray, P. et al. NOD2 is a negative regulator of Toll-like receptor 2–mediated T helper type 1 responses. Nat Immunol 5, 800–808 (2004) doi:10.1038/ni1092
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