Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages.
Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages.
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DOI：
10.1111/j.1476-5381.2010.00814.x
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发表时间：
2010-08
影响因子：
7.3
通讯作者：
Mitchell JA
中科院分区：
文献类型：
--
作者：
Moreno L;McMaster SK;Gatheral T;Bailey LK;Harrington LS;Cartwright N;Armstrong PC;Warner TD;Paul-Clark M;Mitchell JA
革兰氏阴性菌含有toll样受体（TLR） 4和核苷酸寡聚结构域（NOD） 1受体的配体。脂多糖（LPS）激活TLR4，而肽聚糖产物激活NOD1。特异性激动剂FK565激活NOD1可导致体内严重的血管功能障碍和实验性休克。在这里，我们分析了一些药理学抑制剂，以表征TLR4或NOD1激活后诱导NOS2的关键信号通路的作用。血管平滑肌（VSM）细胞表达NOD1 mRNA和蛋白，经大肠杆菌或FK565攻毒后，可诱导NOS2蛋白表达和活性。巨噬细胞的NOD1水平可以忽略不计，不受FK565的影响，但对大肠杆菌和LPS的反应是释放更多的NO和表达NOS2蛋白。NF-κB （SC-514）和丝裂原活化蛋白激酶（SB203580, PD98059）信号通路的经典药物抑制剂抑制两种细胞类型的反应，而不考虑激动剂。泛caspase抑制剂z-VAD-fmk和PKC抑制剂Gö6976特异性抑制巨噬细胞中tlr4介导的应答，而Rip2抑制剂PP2抑制VSM细胞中nod1介导的应答。我们的研究结果表明NOD1在VSM细胞中具有选择性作用，并强调NOD1是治疗血管炎症的潜在新治疗靶点。
Gram-negative bacteria contain ligands for Toll-like receptor (TLR) 4 and nucleotide oligomerization domain (NOD) 1 receptors. Lipopolysaccharide (LPS) activates TLR4, while peptidoglycan products activate NOD1. Activation of NOD1 by the specific agonist FK565 results in a profound vascular dysfunction and experimental shock in vivo. Here, we have analysed a number of pharmacological inhibitors to characterize the role of key signalling pathways in the induction of NOS2 following TLR4 or NOD1 activation. Vascular smooth muscle (VSM) cells expressed NOD1 mRNA and protein, and, after challenge with Escherichia coli or FK565, NOS2 protein and activity were induced. Macrophages had negligible levels of NOD1 and were unaffected by FK565, but responded to E. coli and LPS by releasing increased NO and expression of NOS2 protein. Classic pharmacological inhibitors for NF-κB (SC-514) and mitogen-activated protein kinase (SB203580, PD98059) signalling pathways inhibited responses in both cell types regardless of agonist. While TLR4-mediated responses in macrophages were specifically inhibited by the pan-caspase inhibitor z-VAD-fmk and the PKC inhibitor Gö6976, NOD1-mediated responses in VSM cells were inhibited by the Rip2 inhibitor PP2. Our findings suggest a selective role for NOD1 in VSM cells, and highlight NOD1 as a potential novel therapeutic target for the treatment of vascular inflammation.
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影响因子：
4.8
作者：
Garcia-Calvo, M;Peterson, EP;Thornberry, NA
通讯作者：
Thornberry, NA
DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
7
作者：
Shaw, Michael H.;Reimer, Thornik;Kim, Yun-Gi;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
4.8
作者：
Asehnoune, K;Strassheim, D;Abraham, E
通讯作者：
Abraham, E
影响因子：
7.3
作者：
Paul-Clark, Mark J.;Mc Master, Shaun K.;Mitchell, Jane A.
通讯作者：
Mitchell, Jane A.