CONSTITUTIVE NF-KAPPA-B ACTIVITY IN NEURONS
CONSTITUTIVE NF-KAPPA-B ACTIVITY IN NEURONS
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DOI：
10.1128/mcb.14.6.3981
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发表时间：
1994-06-01
影响因子：
5.3
通讯作者：
BAEUERLE, PA
中科院分区：
文献类型：
--
作者：
KALTSCHMIDT, C;KALTSCHMIDT, B;BAEUERLE, PA
NF-κ B是一种诱导型转录因子，以潜在的细胞质形式存在于许多细胞类型中。到目前为止，只有免疫细胞，包括成熟的B细胞，胸腺细胞，和粘附巨噬细胞已被报道含有组成型活性形式的NF-κ B在核中。最近的一项研究表明，人类免疫缺陷病毒1型（HIV-1）启动子在转基因小鼠的几个脑区高度活跃（J. R. Corboy，J. M.巴兹，M。C. Zink和J.E. Clements，Science 258：1804-1807，1992）。由于这种病毒增强子的活性主要受NF-κ B的两个结合位点的控制，因此我们被提示研究神经元中NP-κ B活性的状态。来自大鼠海马和大脑皮质的原代神经元培养物显示HIV-1长末端重复驱动的荧光素酶报告基因的高组成型表达，其主要依赖于完整的NF-κ B B结合位点，并且在NF-κ B特异性抑制剂I κ B-α的共表达后被废除。间接免疫荧光和激光共聚焦显微镜显示，NF-κ B B的活性与NF-κ B B亚单位p50和RelA（p65）在培养的神经元细胞核中的存在相关。NF-κ B在体内神经元中也具有组成性活性。如通过电泳迁移率变动测定所研究的，组成型NF-κ B DNA结合活性在从大鼠大脑皮质制备的含有神经元核的组分中高度富集。在小鼠大脑皮层和海马的冷冻切片中也观察到核NF-κ B特异性免疫染色。只有一部分神经元被染色。脑中活化的NF-κ B可能参与正常的脑功能并反映神经元活性或分化的不同状态。此外，它可以解释神经元中HIV-1增强子的高水平活性，这一观察结果可能与中枢神经系统HIV感染引起的AIDS痴呆综合征的病因学有关。
NF-kappa B is an inducible transcription factor present in many cell types in a latent cytoplasmic form. So far, only immune cells including mature B cells, thymocytes, and adherent macrophages have been reported to contain constitutively active forms of NF-kappa B in the nucleus. A recent study showed that the human immunodeficiency virus type 1 (HIV-1) promoter is highly active in several brain regions of transgenic mice (J. R. Corboy, J. M. Buzy, M. C. Zink, and J. E. Clements, Science 258:1804-1807, 1992). Since the activity of this viral enhancer is governed mainly by two binding sites for NF-kappa B, we were prompted to investigate the state of NP-kappa B activity in neurons. Primary neuronal cultures derived from rat hippocampus and cerebral cortex showed a high constitutive expression of an HIV-1 long terminal repeat-driven luciferase reporter gene, which was primarily dependent on intact NF-kappa B binding sites and was abolished upon coexpression of the NF-kappa B-specific inhibitor I kappa B-alpha. Indirect immunofluorescence and confocal laser microscopy showed that the activity of NF-kappa B correlated with the presence of the NF-kappa B subunits p50 and RelA (p65) in nuclei of cultured neurons. NF-kappa B was also constitutively active in neurons in vivo. As investigated by electrophoretic mobility shift assays, constitutive NF-kappa B DNA-binding activity was highly enriched in fractions containing neuronal nuclei prepared from rat cerebral cortex. Nuclear NF-kappa B-specific immunostaining was also seen in cryosections from mouse cerebral cortex and hippocampus. Only a subset of neurons was stained. Activated NF-kappa KB in the brain is likely to participate in normal brain function and to reflect a distinct state of neuronal activity or differentiation. Furthermore, it may explain the high level of activity of the HIV-1 enhancer in neurons, an observation potentially relevant for the etiology of the AIDS dementia complex caused by HIV infection of the central nervous system.