Oxidative-nitrosative stress and post-translational protein modifications:: Implications to lung structure-function relations -: Arginase modulates NF-κB activity via a nitric oxide-dependent mechanism
Oxidative-nitrosative stress and post-translational protein modifications:: Implications to lung structure-function relations -: Arginase modulates NF-κB activity via a nitric oxide-dependent mechanism
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DOI：
10.1165/rcmb.2006-0329sm
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发表时间：
2007-06-01
影响因子：
6.4
通讯作者：
Janssen-Heininger, Yvonne
中科院分区：
文献类型：
--
作者：
Ckless, Karina;van der Vliet, Albert;Janssen-Heininger, Yvonne
NF-kappa B是一种多功能转录因子，可调节多种过程，包括炎症和生存，并在炎症性肺部疾病的病因学中起关键作用。一氧化氮（NO）已被认为通过nf - κ B通路组分的s -亚硝化作用发挥抗炎作用。NO的产生可以通过改变其底物l -精氨酸的可用性来调节。精氨酸酶与NO合成酶（nos）竞争其共同的底物l -精氨酸，因此有可能改变NO的信号功能。本研究的目的是确定精氨酸酶操作对肺上皮细胞NO的影响，以及随后对NF-kB活化的影响。我们的研究结果表明，精氨酸酶活性的降低增加了NO和s -亚硝化蛋白的细胞含量，并导致tnf - α或lps刺激的NF-kB DNA结合和转录活性的降低，这与p50的s -亚硝化增强有关。精氨酸酶抑制nf - κ B的作用可被NOS抑制剂n -omega-硝基- l -精氨酸甲酯（L-NAME）逆转，提示NO在精氨酸酶抑制诱导的NF-kB衰减中起因果作用。相反，精氨酸酶I的过表达降低了细胞s -亚硝基硫醇含量，增强了I κ B激酶活性和NF-kB DNA结合，降低了p50的s -亚硝基化。总的来说，我们的数据指出了一种调节机制，其中NF-kB是通过精氨酸酶依赖的NO水平调节来控制的，这可能影响伴随NF-kB激活和精氨酸酶上调的慢性炎症性疾病。
NF-kappa B is a versatile transcription factor that regulates a wide array of processes, including inflammation and survival, and plays a critical role in the etiology of inflammatory lung diseases. Nitric oxide (NO) has been suggested to play an antiinflammatory role through S-nitrosation of components of NF-kappa B pathway. NO production can be modulated by changing the availability of its substrate, L-arginine. Arginases compete with NO synthases (NOSs) for their common substrate, L-arginine, and thereby have the potential to alter the signaling function of NO. The goal of the present study was to determine the impact of arginase manipulation on NO, and subsequent effects on NF-kB activation, in lung epithelial cells. Our results demonstrate that reduction of arginase activity enhanced cellular content of NO and S-nitrosated proteins, and resulted in decreases in TNF-alpha- or LPS-stimulated NF-kB DNA binding and transcriptional activity, in association with enhanced S-nitrosation of p50. The effects of arginase inhibition on NF-kappa B were reversed by the generic NOS inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), suggesting a causal role for NO in the attenuation of NF-kB induced by arginase suppression. Conversely, overexpression of arginase I decreased cellular S-nitrosothiol content and enhanced I kappa B kinase activity and NF-kB DNA binding, and decreased S-nitrosation of p50. Collectively, our data point to a regulatory mechanism wherein NF-kB is controlled through arginase-dependent regulation of NO levels, which may impact on chronic inflammatory diseases that are accompanied by NF-kB activation and upregulation of arginases.