Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-κB activation
Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-κB activation
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DOI：
10.1074/jbc.m206473200
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发表时间：
2002-11-01
影响因子：
4.8
通讯作者：
Fernandez-Luna, JL
中科院分区：
文献类型：
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作者：
Gutierrez, O;Pipaon, C;Fernandez-Luna, JL
NOD2是Apaf1/NOD蛋白家族的一员，负责对细菌产物的反应性，并激活转录因子NF-kappaB，后者在先天免疫中发挥核心作用。最近，NOD2的基因变异与克罗恩病的易感性有关。在此，我们报道了CD34(+)造血祖细胞分化为粒细胞或单核/巨噬细胞后，NOD2的表达被诱导。在外周血细胞中，CD14(+)(单核细胞)、CD15(+)(粒细胞)和CD40(+)/CD86(+)(树突状细胞)细胞群的NOD2水平最高。值得注意的是，细菌脂多糖或肿瘤坏死因子α刺激成髓细胞和上皮细胞可导致NOD2的上调。对NOD2启动子内的共有位点的搜索发现了一个核因子-kappaB结合元件，这是响应TNFpha的转录活性所必需的。此外，p65的异位表达诱导了反式激活，而显性负性IkappaBalpha的异位表达则阻断了NOD2启动子的转录活性。在肿瘤坏死因子α或脂多糖刺激下，核因子-kappaB的p50和p65亚基都与NOD2启动子结合。因此，促炎细胞因子和细菌成分通过核因子-kappaB促进NOD2的表达，这一机制可能有助于放大先天免疫反应和对炎症性疾病的易感性。
Nod2, a member of the Apaf1/Nod protein family, confers responsiveness to bacterial products and activates NF-kappaB, a transcription factor that plays a central role in innate immunity. Recently, genetic variation in Nod2 has been associated with susceptibility to Crohn's disease. Here, we report that expression of Nod2 is induced upon differentiation of CD34(+) hematopoietic progenitor cells into granulocyte or monocyte/macrophages. In peripheral blood cells, the highest levels of Nod2 were observed in CD14(+) (monocytes), CD15(+) (granulocytes), and CD40(+)/CD86(+) (dendritic cells) cell populations. Notably, stimulation of myeloblastic and epithelial cells with bacterial lipopolysaccharide or TNFalpha resulted in up-regulation of Nod2. A search for consensus sites within the Nod2 promoter revealed a NF-kappaB binding element that was required for transcriptional activity in response to TNFalpha. Moreover, ectopic expression of p65 induced transactivation, whereas that of dominant-negative IkappaBalpha blocked the transcriptional activity of the Nod2 promoter. Upon stimulation with TNFalpha or lipopolysaccharide, both p50 and p65 subunits of NF-kappaB were bound to the Nod2 promoter. Thus, Nod2 expression is enhanced by proinflammatory cytokines and bacterial components via NF-kappaB, a mechanism that may contribute to the amplification of the innate immune response and susceptibility to inflammatory disease.