Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor κBα within specific cellular populations of the rat brain
Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor κBα within specific cellular populations of the rat brain
复制标题
DOI：
10.1046/j.1471-4159.1999.0730309.x
复制
发表时间：
1999-07-01
影响因子：
4.7
通讯作者：
Rivest, S
中科院分区：
文献类型：
--
作者：
Laflamme, N;Rivest, S
抑制因子kappa B α (I kappa B α)的表达反映了核因子kappa B（NF-kappa B）的活性，是研究中枢神经系统内转录因子调控的有力工具。采用原位杂交法测定不同免疫原性刺激下大鼠脑内kappa B α mRNA的表达；即，腹腔注射（i.p）和静脉注射（i.v）脂多糖（LPS），静脉注射重组大鼠白细胞介素（[L） 1 β， IL-6或肿瘤坏死因子- α (tnf - α)，以及肌肉注射（i.m）松节油，在这里用作全身性局部炎症损伤的模型。系统性LPS、IL-1 β和tnf - α引起沿整个大脑血管的I κ B α快速和短暂的转录激活；信号在静脉注射后30-60分钟非常强烈，并在2 - 12小时内恢复到不可检测的水平，这取决于挑战。双重标记程序提供了解剖学证据，表明微血管内表达I κ B α的细胞本质上是内皮型的，因为它们对血管性血液病因子具有免疫反应。注射LPS-、IL-1 β -和tnf -的大鼠在1-3小时内也发现了分散的小细胞，小胶质细胞（OX-42）免疫反应细胞对转录产物呈阳性。然而，在局部无菌炎症损伤后的脑实质小胶质细胞中没有观察到这种表达。事实上，注射松节油对脑毛细血管内皮内I κ pa B α转录的刺激非常独特，这种效果与注射部位的肿胀平行，并在攻击后持续24小时。与这些免疫原性挑战相反，静脉注射IL-6未能激活大鼠大脑中编码I κ B α的基因。这些结果表明，NF-kappa B可能在中枢神经系统的特定细胞群中发挥关键作用，触发免疫相关基因的转录，并且I -kappa B α再合成可能作为一种动态的细胞内抑制反馈，以避免反应的夸大。可能血脑屏障细胞中的I κ B α表达是全身性炎症期间发生的一般机制，而中枢神经系统实质细胞中nf - κ B相关分子的参与是在更严重的情况下（如血液败血症和内毒素血症）引起的。
Expression of the inhibitory factor kappa B alpha (I kappa B alpha) reflects the activity of nuclear factor kappa B(NF-kappa B) and is a powerful tool to investigate the regulation of the transcription factor within the CNS. I kappa B alpha mRNA was evaluated in the rat brain by means of in situ hybridization following different immunogenic stimuli; i.e., intraperitoneal (i.p,) and intravenous (i.v.) lipopolysaccharide (LPS), i.v. recombinant rat interleukin ([L) 1 beta, IL-6, or tumor necrosis factor-alpha (TNF-alpha), and intramuscular (i.m.) turpentine injection, used here as a model of systemic localized inflammatory insult. Systemic LPS, IL-1 beta, and TNF-alpha caused a rapid and transient transcriptional activation of I kappa B alpha along the blood vessels of the entire brain; the signal was very intense 30-60 min after the i.v. injections and returned to undetectable levels from 2 to 12 h depending on the challenge, Double-labeling procedure provided the anatomical evidence that I kappa B alpha-expressing cells within the microvasculature were essentially of the endothelial type, as they were immunoreactive to the von Willebrand factor. Scattered small cells were also found across the brain of LPS-, IL-1 beta-, and TNF-alpha-injected rats at time 1-3 h, and microglial (OX-42)immunoreactive cells were positive for the transcript. Such expression within parenchymal microglia was nevertheless not observed in the brain following a localized and sterile inflammatory insult. indeed, i.m. turpentine administration stimulated I kappa B alpha transcription quite uniquely within the endothelium of the brain capillaries, an effect that paralleled the swelling of the injection site and lasted up to 24 h after the aggression. In contrast to these immunogenic challenges, i.v. IL-6 injection failed to activate the gene encoding I kappa B alpha in the rat brain. These results indicate that NF-kappa B may play a crucial role in specific cellular populations of the CNS to trigger transcription of immune-related genes and that I kappa B alpha resynthesis may act as a dynamic intracellular inhibitory feedback to avoid exaggeration of the response. It is possible that I kappa B alpha expression in cells of the blood-brain barrier is a general mechanism that takes place during systemic inflammation, whereas the participation of NF-kappa B-related molecules within parenchymal cells of the CNS is solicited during more severe conditions such as blood sepsis and endotoxemia.