Bierhaus Angelika, Wolf Jutta, Andrassy Martin, Rohleder Nicolas, Humpert Per M, Petrov Dimitri, Ferstl Roman, von Eynatten Maximilian, Wendt Thoralf, Rudofsky Gottfried, Joswig Martina, Morcos Michael, Schwaninger Markus, McEwen Bruce, Kirschbaum Clemens, Nawroth Peter P
Department of Medicine I, University of Heidelberg, Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1920-5. doi: 10.1073/pnas.0438019100. Epub 2003 Feb 10.
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, noradrenaline-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.
关于将心理社会压力转化为细胞功能障碍的机制，目前所知甚少。多种基因在动脉粥样硬化中上调，在心理社会压力作用下也会上调，它们受转录因子核因子κB（NF-κB）控制。因此，NF-κB是将心理社会压力转化为细胞激活的一个很好的候选因素。志愿者接受了一项简短的实验室压力测试，并测定外周血单核细胞（PBMC）中的NF-κB活性，PBMC可作为了解身体内部情况的窗口，且其在动脉粥样硬化等疾病中发挥作用。在19名志愿者中的17名中，NF-κB在压力暴露期间迅速被诱导，同时儿茶酚胺和皮质醇水平升高，并在60分钟内恢复到基础水平。为模拟这种反应，对携带严格受NF-κB控制的β-珠蛋白转基因的小鼠进行固定应激。固定导致β-珠蛋白表达增加，在α1-肾上腺素能抑制剂哌唑嗪存在的情况下这种增加可被降低。为确定肾上腺素能刺激在NF-κB上调中的作用，用生理量的儿茶酚胺诱导THP-1细胞10分钟。只有去甲肾上腺素导致NF-κB和NF-κB依赖性基因表达呈剂量和时间依赖性诱导，这依赖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的激活。α1-和β-肾上腺素能抑制剂可减少诱导。因此，去甲肾上腺素依赖性肾上腺素能刺激在体外和体内均可导致NF-κB激活。NF-κB的激活代表了对压力性心理社会事件的神经内分泌反应的下游效应器，并将神经内分泌轴活性的变化与细胞反应联系起来。
