A mechanism converting psychosocial stress into mononuclear cell activation
A mechanism converting psychosocial stress into mononuclear cell activation
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DOI：
10.1073/pnas.0438019100
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发表时间：
2003-02-18
影响因子：
11.1
通讯作者：
Nawroth, PP
中科院分区：
文献类型：
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作者：
Bierhaus, A;Wolf, J;Nawroth, PP
人们对心理社会压力转化为细胞功能障碍的机制知之甚少。各种基因，上调动脉粥样硬化，但也由心理社会压力，是由转录因子核因子κ B（NF-κ B）控制。因此，NF-kappaB是将心理社会应激转化为细胞激活的良好候选者。志愿者接受了简短的实验室应激试验，并在外周血单核细胞（PBMC）中测定了NF-κ B活性，作为进入身体的窗口，因为PBMC在动脉粥样硬化等疾病中发挥作用。在19名志愿者中的17名，NF-κ B在应激暴露过程中迅速诱导，与儿茶酚胺和皮质醇水平升高平行，并在60分钟内恢复到基础水平。为了模拟这种反应，小鼠转基因严格NF-κ B控制的β-珠蛋白转基因强调固定。固定导致β-珠蛋白的表达增加，这可以减少在α 1-肾上腺素能抑制剂哌唑嗪的存在。要确定的作用，肾上腺素能刺激的上调NF-κ B，THP-1细胞诱导与生理量的儿茶酚胺10分钟。只有去甲肾上腺素导致剂量和时间依赖性诱导NF-κ B和NF-κ B依赖的基因表达，这取决于百日咳毒素敏感的G蛋白介导的磷脂酰肌醇3-激酶，Ras/Raf，和丝裂原活化蛋白激酶激活。α（1）-和β-肾上腺素能抑制剂可降低诱导作用。因此，去甲肾上腺素依赖性肾上腺素能刺激导致体外和体内NF-κ B活化。NF-kappaB的激活代表了神经内分泌对应激性心理社会事件的反应的下游效应物，并将神经内分泌轴的活性变化与细胞反应联系起来。
Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, norad renaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.