High Constitutive NFk B Activity Mediates Resistance to Oxidative Stress in Neuronal Cells
High Constitutive NFk B Activity Mediates Resistance to Oxidative Stress in Neuronal Cells
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发表时间：
1998
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通讯作者：
F. Lezoualc’h;Y. Sagara;F. Holsboer;C. Behl
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作者：
F. Lezoualc’h;Y. Sagara;F. Holsboer;C. Behl
交感神经前体样细胞系 PC12 (rCl8) 的选定克隆能够抵抗阿尔茨海默病相关的淀粉样蛋白 b 蛋白 (Ab) 和过氧化氢 (H2O2) 诱导的氧化细胞死亡。在这里，我们发现，与非耐药亲本 PC12 细胞（PC12p）对应物相比，rCl8 细胞中氧化还原敏感转录因子 NF-kB 的转录活性和 DNA 结合活性及其核表达持续增加。用合成的糖皮质激素地塞米松或直接过度表达 IkBa（一种 NF-kB 特异性抑制剂）的超级阻遏突变体形式来抑制 rCl8 细胞中 NF-kB 的转录活性，逆转了这些细胞的氧化应激抵抗表型，并最终导致 H2O2 攻击后细胞死亡增加。地塞米松治疗还导致 IkBa 蛋白水平增加。我们的数据表明，NF-kB 活性基线的增加可能介导这些神经元来源的细胞对氧化应激的抵抗力。因此，所提出的模型可能有助于识别 NF-kB 可能的神经元靶基因，并进一步阐明与氧化负担增加相关的神经退行性疾病（例如阿尔茨海默病）中神经元差异敏感性的分子基础。
Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are resistant to oxidative cell death induced by the Alzheimer’s disease-associated amyloid b protein (Ab) and hydrogen peroxide (H2O2). Here, we show that the transcriptional activity and DNA binding activity of the redox-sensitive transcription factor NF-kB and its nuclear expression are constitutively increased in rCl8 cells compared with their nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the transcriptional activity of NF-kB in rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct overexpression of a super-repressor mutant form of IkBa, a specific inhibitor of NF-kB, reversed the oxidative stress resistance phenotype of these cells and ultimately led to increased cell death after the challenge with H2O2. Dexamethasone treatment also caused an increase in the protein level of IkBa. Our data show that an increased baseline of NF-kB activity may mediate the resistance of these cells of neuronal origin to oxidative stress. Therefore, the presented model may help to identify possible neuronal target genes of NF-kB and to further elucidate the molecular basis of the differential sensitivity of neurons in neurodegenerative conditions associated with an increased oxidative burden, such as in Alzheimer’s disease.