Laflamme N, Lacroix S, Rivest S
Laboratory of Molecular Endocrinology, Centre de Recherche de l'Université Laval Research Center, Department of Anatomy, Laval University, Québec, Canada G1V 4G2.
J Neurosci. 1999 Dec 15;19(24):10923-30. doi: 10.1523/JNEUROSCI.19-24-10923.1999.
When released into the bloodstream, proinflammatory cytokines have the ability to trigger the transcription of different genes in cells of the blood-brain barrier (BBB), including members of the nuclear factor kappa B (NF-kappaB) family and cyclooxygenase-2 (COX-2), the limiting enzyme for the formation of prostaglandins (PGs). The present study investigated the possibility that interleukin-1beta (IL-1beta) plays an essential role in these events during a systemic inflammatory response. Both wild-type and IL-1beta-deficient mice were killed at different times after two different immunogenic stimuli, i.e., intraperitoneal lipopolysaccharide (LPS) injection and intramuscular turpentine injection, used here as a model of systemic localized inflammatory insult. The inhibitory factor kappaBalpha (IkappaBalpha, index of NF-kappaB activity) and COX-2 transcripts were detected throughout the brain by means of in situ hybridization. Systemic LPS injection caused a strong and rapid expression of IkappaBalpha in endothelial cells lining the BBB of large and small blood vessels and thereafter within parenchymal microglia across the brain. This treatment also provoked a transient expression of COX-2 along cells of the vascular system, and the expression pattern and intensity of the signal for both transcripts were essentially the same in wild-type and IL-1beta-deficient animals. In contrast, the induction of these genes that was quite selective to the cells of the BBB in response to intramuscularly turpentine insult was completely abolished in IL-1beta-deficient mice. Indeed, a late and prolonged expression of IkappaBalpha and COX-2 mRNAs was found along the cerebral blood vessels in response to the sterile and localized inflammation in wild-type mice, whereas such induction was absent in the brain of IL-1beta-deficient animals. These results indicate that IL-1beta has an obligatory role in the activation of NF-kappaB molecules and PGs within endothelial cells of the BBB in an experimental model of intramuscularly turpentine-induced inflammation but not during endotoxemia.
当促炎细胞因子释放到血液中时，它们能够触发血脑屏障（BBB）细胞中不同基因的转录，包括核因子κB（NF-κB）家族成员和环氧化酶-2（COX-2），后者是前列腺素（PGs）形成的限速酶。本研究调查了白细胞介素-1β（IL-1β）在全身炎症反应期间的这些事件中是否发挥重要作用。在两种不同的免疫原性刺激（即腹腔注射脂多糖（LPS）和肌肉注射松节油）后，在不同时间处死野生型和IL-1β缺陷型小鼠，这里将其用作全身局部炎症损伤的模型。通过原位杂交在整个大脑中检测抑制因子κBα（IkappaBalpha，NF-κB活性指标）和COX-2转录本。全身注射LPS导致大小血管BBB内衬的内皮细胞中IkappaBalpha强烈且快速表达，随后在整个大脑的实质小胶质细胞中表达。这种处理还引发了COX-2在血管系统细胞中的瞬时表达，并且在野生型和IL-1β缺陷型动物中，两种转录本信号的表达模式和强度基本相同。相比之下，在IL-1β缺陷型小鼠中，对肌肉注射松节油损伤的反应中，这些对BBB细胞具有高度选择性的基因诱导完全被消除。事实上，在野生型小鼠中，响应无菌性局部炎症，在脑血管中发现了IkappaBalpha和COX-2 mRNA的晚期和延长表达，而在IL-1β缺陷型动物的大脑中则没有这种诱导。这些结果表明，在肌肉注射松节油诱导的炎症实验模型中，IL-1β在BBB内皮细胞内NF-κB分子和PGs的激活中起必要作用，但在内毒素血症期间不起作用。
