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.
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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.
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skos:exactMatch | |
uniprot:name |
Nat. Immunol.
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uniprot:author |
Kitani A.,
Murray P.J.,
Strober W.,
Watanabe T.
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uniprot:date |
2004
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uniprot:pages |
800-808
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uniprot:title |
NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.
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uniprot:volume |
5
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dc-term:identifier |
doi:10.1038/ni1092
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