NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses
NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses
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DOI：
10.1038/ni1092
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发表时间：
2004-08-01
影响因子：
30.5
通讯作者：
Strober, W
中科院分区：
文献类型：
--
作者：
Watanabe, T;Kitani, A;Strober, W
编码核苷酸结合寡聚化结构域2（NOD 2）的CARD 15突变导致克罗恩病的机制知之甚少。由于通过突变的NOD 2蛋白的信号传导导致转录因子NF-κ B的缺陷性激活，一种观点认为突变导致NF-κ B依赖性T辅助细胞1型（T（H）1）应答缺陷和感染易感性增加。然而，这一想法与克罗恩病的T（H）1反应增加的特征不一致。在这里，我们使用Card 15（-/-）小鼠来显示完整的NOD 2信号传导抑制Toll样受体2驱动的NF κ B活化，特别是NF-κ B亚基c-Rel。此外，NOD 2缺陷或克罗恩病样Card 15突变的存在增加了Toll样受体2介导的NF-κ B-c-Rel活化，并且T（H）1应答增强。因此，CARD 15突变可能通过引起过度的T（H）1反应而导致疾病。
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-kappaB, one proposal is that mutations cause deficient NF-kappaB-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 NFkappaB, particularly of the NF-kappaB 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-kappaB-c-Rel, and T(H)1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive T(H)1 responses.