Mechanisms of the Inhibition of Nuclear Factor-κB by Morphine in Neuronal Cells
Mechanisms of the Inhibition of Nuclear Factor-κB by Morphine in Neuronal Cells
复制标题
DOI：
10.1124/mol.111.076620
复制
发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Kraus, Juergen
中科院分区：
文献类型：
--
作者：
Boerner, Christine;Hoellt, Volker;Kraus, Juergen
阿片类药物有效地调节神经元功能，例如，通过调节转录因子的活性。在这里，我们研究了吗啡对转录因子核因子κ B（NF-κ B）活性的影响。建立细胞模型，我们的调查，我们证明，NF-κ B介导的肿瘤坏死因子（TNF）诱导的大麻素受体1型基因在大鼠和人神经母细胞瘤细胞系SH SY 5 Y的原代胎儿纹状体神经元的转录。在这些模型中，NF-κ B的活性被吗啡强烈抑制，这是通过核因子-κ B抑制剂（I κ B）的显著上调实现的。阿片诱导的I κ B上调依赖于转录因子NF-κ B本身和激活蛋白1（AP-1）。事实上，用吗啡刺激细胞导致NF-κ B的瞬时激活和AP-1的成分之一c-Fos的强烈诱导。这导致I κ B水平显著超过I κ B的基础组成性水平。这些数据，以及AP-1和I κ B被诱饵寡核苷酸和siRNA下调的实验，表明吗啡诱导的AP-1激活和随后的I κ B过表达是药物抑制NF-κ B的关键因素。相反，用TNF刺激大鼠和SH SY 5 Y细胞的原代神经元，TNF是NF-κ B的经典激活剂，导致I κ B的再合成，其中I κ B的基础水平仅恢复，但不导致AP-1的激活和I κ B的过表达。
Opioids potently modulate neuronal functions, for example, by regulating the activity of transcription factors. Here, we investigated the effect of morphine on the activity of the transcription factor nuclear factor kappa B (NF-kappa B). Establishing cellular models for our investigations, we demonstrated that NF-kappa B mediated the tumor necrosis factor (TNF)-induced transcription of the cannabinoid receptor type 1 gene in primary fetal striatal neurons from rats and the human neuroblastoma cell line SH SY5Y. The activity of NF-kappa B in these models was strongly inhibited by morphine, which was achieved by a marked up-regulation of the inhibitor of nuclear factor-kappa B (I kappa B). The opioid-induced up-regulation of I kappa B was dependent on the transcription factors NF-kappa B itself and activator protein-1 (AP-1). In fact, stimulation of the cells with morphine resulted in a transient activation of NF-kappa B and a strong induction of c-Fos, one of the constituents of AP-1. This resulted in I kappa B levels significantly exceeding the basal, constitutive levels of I kappa B. These data, together with experiments in which AP-1 and I kappa B were down-regulated by decoy oligonucleotides and siRNA, suggest that the morphine-induced activation of AP-1 and the subsequent overexpression of I kappa B are key factors in the inhibition of NF-kappa B by the drug. In contrast, stimulation of primary neurons from rats and SH SY5Y cells with TNF, which is a classic activator of NF-kappa B, resulted in a resynthesis of I kappa B, in which the basal levels of I kappa B were restored only but did not result in an activation of AP-1 and overexpression of I kappa B.