Rho A negatively regulates cytokine-mediated inducible nitric oxide synthase expression in brain-derived transformed cell lines:: Negative regulation of IKKα
Rho A negatively regulates cytokine-mediated inducible nitric oxide synthase expression in brain-derived transformed cell lines:: Negative regulation of IKKα
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DOI：
10.1016/s0891-5849(03)00459-3
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发表时间：
2003-11-01
影响因子：
7.4
通讯作者：
Singh, I
中科院分区：
文献类型：
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作者：
Rattan, R;Giri, S;Singh, I
本研究描述了RhoA通过在转化脑细胞系[C-6胶质瘤、人星形细胞瘤（T98 G、A172）、神经母细胞瘤（NEB）和永生大鼠星形细胞]中灭活NF-κ B作为iNOS表达的负调节剂的作用。用洛伐他汀处理导致诱导LPS/IFN-γ介导的iNOS mRNA和增加一氧化氮（NO）的产生。甲羟戊酸和香叶基香叶基焦磷酸（GGPP）的加入逆转了洛伐他汀介导的作用，而FPP没有影响。香叶基香叶基转移酶抑制剂（GGTI 298）的抑制剂进一步诱导细胞因子和lovastatin介导的iNOS表达，表明香叶基香叶基化蛋白参与iNOS的调节。细菌毒素B（灭活RhoA、B和C; CDC 42; Rac蛋白），来自C的C3 ADP-核糖基转移酶（0）毒素。肉毒杆菌（灭活RhoA、B和C蛋白）和Y-27632（Rho相关激酶的选择性抑制剂）增加LPS/IFN-γ介导的iNOS表达。洛伐他汀处理通过增加NF-κ B易位及其与CREB结合蛋白（CBP/p300）的相关性（通过下调RhoA）诱导NO。RhoA的抑制导致IKK α的活化增加。用显性阴性形式的RhoA和iNOS-荧光素酶或NF-κ B-荧光素酶报告基因构建体的共转染研究进一步支持这些观察结果。总之，这些研究表明，通过洛伐他汀下调RhoA导致转化脑细胞中通过NF-κ B-CBP/p300通路的激活增加iNOS表达。(C)2003年爱思唯尔公司
The present study describes the role of RhoA as a negative regulator of iNOS expression via the inactivation of NF-kappaB in transformed brain cell lines [C-6 glioma, human astrocytoma (T98G, A172), neuroblastoma (NEB), and immortal rat astrocytes]. Treatment with lovastatin resulted in the induction of LPS/IFN-gamma-mediated iNOS mRNA and increased nitric oxide (NO) production. The addition of mevalonate and geranylgeranylpyrophosphate (GGPP) reversed the lovastatin-mediated effect, whereas FPP had no effect. An inhibitor of geranylgeranyltransferase inhibitor (GGTI 298) further induced the cytokine and lovastatin-mediated iNOS expression, suggesting the involvement of geranylgeranylated proteins in the regulation of iNOS. Bacterial toxin B (inactivates RhoA, B, and C; CDC42; Rac proteins), C3 ADP-ribosyltransferase (0) toxin from C. botulinum (inactivates RhoA, B, and C proteins), and Y-27632 (selective inhibitor of Rho-associated kinases) increased the LPS/IFN-gamma-mediated iNOS expression. Lovastatin treatment induced NO by increasing NF-kappaB translocation and its association with the CREB-binding protein (CBP/p300) via the downregulation of RhoA. Inhibition of RhoA resulted in increased activation of IKKalpha. Cotransfection studies with dominant-negative form of RhoA and iNOS-luciferase or NF-kappaB-luciferase reporter constructs further support these observations. Taken together, these studies show that downregulation of RhoA by lovastatin resulted in increased iNOS expression via the activation of NF-kappaB-CBP/p300 pathway in transformed brain cells. (C) 2003 Elsevier Inc.