Vitamin C suppresses TNFα-induced NFκB activation by inhibiting IκBα phosphorylation
Vitamin C suppresses TNFα-induced NFκB activation by inhibiting IκBα phosphorylation
复制标题
DOI：
10.1021/bi0263210
复制
发表时间：
2002-10-29
期刊：
影响因子：
2.9
通讯作者：
Golde, DW
中科院分区：
文献类型：
--
作者：
Cárcamo, JM;Pedraza, A;Golde, DW
细胞外刺激信号激活转录因子NF κ B，导致参与免疫应答、炎症和细胞存活的基因表达调节过程。肿瘤坏死因子-α（TNF α）通过涉及NF κ B诱导激酶（NIK）的明确的激酶途径激活NF κ B，NIK激活下游多亚基IkappaB激酶（IKK）。IKK反过来磷酸化NF κ B功能的中央调节因子IkappaB。我们发现细胞内维生素C以剂量依赖性方式抑制TNF α诱导的人细胞系（HeLa、单核细胞U937、髓性白血病HL-60和乳腺MCF 7）和原代内皮细胞（HUVEC）中NF κ B的活化。维生素C是一种重要的抗氧化剂，大多数细胞通过转运维生素的氧化形式脱氢抗坏血酸（DHA）在细胞内积累抗坏血酸（AA）。由于抗坏血酸在体外过渡金属存在下是一种强促氧化剂，我们通过将细胞与DHA一起孵育来加载维生素C。负载维生素C的细胞显示TNF α诱导的NF κ B核转位、NF κ B依赖性报告基因转录和I κ B α磷酸化显著降低。我们的数据表明，维生素C通过抑制TNF α诱导的NIK和IKK β激酶的激活而抑制NF κ B激活的机制独立于p38 MAP激酶。这些结果表明，细胞内维生素C可以通过抑制NF κ B活化来影响炎症、肿瘤和凋亡过程。
Extracellular stimuli signal for activation of the transcription factor NFkappaB, leading to gene expression regulating processes involved in immune responses, inflammation, and cell survival. Tumor necrosis factor-alpha (TNFalpha) activates NFkappaB via a well-defined kinase pathways involving NFkappaB-inducing kinase (NIK), which activates downstream multisubunit IkappaB kinases (IKK). IKK in turn phosphorylates IkappaB, the central regulator of NFkappaB function. We found that intracellular vitamin C inhibits TNFalpha-induced activation of NFkappaB in human cell lines (HeLa, monocytic U937, myeloid leukemia HL-60, and breast MCF7) and primary endothelial cells (HUVEC) in a dose-dependent manner. Vitamin C is an important antioxidant, and most cells accumulate ascorbic acid (AA) intracellularly by transporting the oxidized form of the vitamin, dehydroascorbic acid (DHA). Because ascorbic acid is a strong pro-oxidant in the presence of transition metals in vitro, we loaded cells with vitamin C by incubating them with DHA. Vitamin C-loaded cells showed significantly decreased TNFa-induced nuclear translocation of NFkappaB, NFkappaB-dependent reporter transcription, and IkappaBalpha phosphorylation. Our data point to a mechanism of vitamin C suppression of NFkappaB activation by inhibiting TNFalpha-induced activation of NIK and IKKbeta kinases independent of p38 MAP kinase. These results suggest that intracellular vitamin C can influence inflammatory, neoplastic, and apoptotic processes via inhibition of NFkappaB activation.