Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells
Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells
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DOI：
10.1152/ajplung.00459.2001
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发表时间：
2002-09-01
影响因子：
4.9
通讯作者：
Kelley, TJ
中科院分区：
文献类型：
--
作者：
Kraynack, NC;Corey, DA;Kelley, TJ
诱导型一氧化氮合酶（NOS 2）的异常失调被认为在许多炎症性疾病中起作用，包括囊性纤维化（CF）。NOS 2表达的复杂调控是深入研究的主题，已知影响NOS 2表达的一个有趣的调控途径是Rho GT3级联。我们研究了在人肺泡上皮细胞系中用Rho GT3通路的不同上游和下游组分的抑制剂处理的炎症细胞因子对NOS 2的调节，以更好地定义潜在的信号传导机制。他汀介导的3-羟基-3-甲基戊二酰辅酶A还原酶抑制增加了NOS 2启动子的精氨酸依赖性激活，通过加入香叶基香叶基焦磷酸可逆转。然而，用Y-27632抑制Rho相关激酶（ROCK）导致NOS 2启动子活性降低，但NOS 2 mRNA和蛋白水平增加。我们的研究结果表明，异戊二烯化事件影响NOS 2启动子活性独立的Rho GTdR途径和Rho GTdR信号通过ROCK介导的抑制NOS 2生产下游的启动子功能的消息和蛋白质水平。
The aberrant dysregulation of the inducible form of nitric oxide synthase (NOS2) is thought to play a role in many inflammatory disorders including cystic fibrosis (CF). The complex regulation of NOS2 expression is the subject of intense investigation, and one intriguing regulatory pathway known to influence NOS2 expression is the Rho GTPase cascade. We examined NOS2 regulation in response to inflammatory cytokines in a human alveolar epithelial cell line treated with inhibitors of different upstream and downstream components of the Rho GTPase pathway to better define potential signaling mechanisms. Statin-mediated 3-hydroxy-3-methylglutaryl-CoA reductase inhibition increased cytokine-dependent activation of the NOS2 promoter, reversible by the addition of geranylgeranyl pyrphosphate. However, inhibition of Rho-associated kinase (ROCK) with Y-27632 resulted in a decrease in NOS2 promoter activity, yet an increase in NOS2 mRNA and protein levels. Our results suggest that prenylation events influence NOS2 promoter activity independently of the Rho GTPase pathway and that Rho GTPase signaling mediated through ROCK suppresses NOS2 production downstream of promoter function at the message and protein level.