Mechanisms of interleukin 6 signaling in astrocytes

摘要 神经炎症是一种关键的中枢神经系统（CNS）反应，可在损伤后保护大脑， 创伤和感染;然而，慢性神经炎症被认为是 神经退行性疾病，如阿尔茨海默病、帕金森病（PD）和多发性硬化症。 炎症过程在免疫系统的细胞中得到了很好的表征，但对如何发生炎症过程知之甚少。 CNS细胞可以引发炎症。神经元和神经胶质细胞是CNS中的常驻细胞，已经报道它们在中枢神经系统（CNS）中的作用。 分泌促炎细胞因子。在中枢神经系统细胞中，星形胶质细胞已成为炎症介质 由于感染和损伤，它们释放各种趋化因子和细胞因子， 并激活外周免疫细胞这就创造了一个重要的界面， 在CNS内引发的病理然后可以反过来调节CNS和CNS中炎症的进展 并且可能存在于全身免疫系统中。我们实验室正在进行的研究表明， 与疾病相关的代谢性神经毒素鱼藤酮具有升高的促炎细胞因子水平 包括在脑提取物中可观察到的白细胞介素6（IL 6）。IL 6是重要的炎症介质， 水平升高与多种神经退行性疾病相关。据报道， 在肿瘤坏死因子（TNF）和白细胞介素1b（IL 1b）的作用下分泌IL 6;然而，我们还不知道 星形胶质细胞是否是鱼藤酮暴露后观察到的IL 6的细胞来源。JAK/STAT信号 转导途径由IL 6激活，并且最近报道包括前馈自分泌环 在神经胶质肿瘤细胞中。如果这种机制存在于促炎性星形胶质细胞中， 由于自我延续的神经炎症被认为有助于正常衰老和疾病的进展， 老年人慢性神经系统疾病。培训方案的一个主要组成部分是执行 - 分子生物学研究，以测试星形胶质细胞是疾病诱导的IL 6的细胞来源的预测， 相关的神经毒素暴露。在这些研究中，我们将确定JAK/STAT信号是否 转导通路被神经毒素激活，并且如果一旦建立，该通路可以在神经细胞中维持。 IL-6依赖的方式后停止暴露。在我们的第二个目标中，我们将使用组织学和 生物化学技术，以确定IL 6/JAK/STAT途径是否在小鼠中被激活和维持 暴露于疾病相关的农药鱼藤酮，并确定是否与药物治疗 JAK/STAT抑制剂可以使鱼藤酮暴露期间和之后小鼠中的IL 6水平正常化。理解 星形胶质细胞和中枢神经系统细胞中IL 6诱导的基本细胞和分子机制， 神经毒性应激可能会发现新的感兴趣的途径，用于检测和治疗神经炎症发生 与正常衰老和疾病有关。

Abstract Neuroinflammation is a key central nervous system (CNS) response that protects the brain following injury, trauma, and infection; however, chronic neuroinflammation is recognized as a pathologic manifestation of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Multiple Sclerosis. The inflammatory process is well characterized in cells of the immune system but less is known about how CNS cells can initiate inflammation. Neurons and glia are resident cells in the CNS that have been reported to secrete pro-inflammatory cytokines. Among CNS cells, astrocytes have emerged as mediators of inflammation resulting from infection and injury where they release various chemokines and cytokines important in recruiting and activating peripheral immune cells. This creates an important interface in which astrocytes detecting pathologies initiated within the CNS can then in turn modulate the progression of inflammation in both the CNS and potentially in the systemic immune system. Ongoing studies in our laboratory indicate that mice ingesting the disease-associated metabolic neurotoxin rotenone have elevated levels of the pro-inflammatory cytokines including interleukin 6 (IL6) observable in brain extracts. IL6 is an important inflammatory mediator whose levels are elevated in association with multiple neurodegenerative disorders. Astrocytes have been reported to secrete IL6 in response to tumor necrosis factor (TNF) and interleukin 1b (IL1b); however, we do not yet know whether astrocytes are the cellular origin of IL6 observed following rotenone exposure. The JAK/STAT signal transduction pathway is activated by IL6 and was recently reported to comprise a feed-forward autocrine loop in glial tumor cells. If such a mechanism existed in pro-inflammatory astrocytes it would be of great interest since self-perpetuating neuroinflammation is posited to contribute to normal aging and the progression of chronic neurologic disorders of the elderly. A major component of the training program will be the execution of molecular biology studies to test the prediction that astrocytes are the cellular origin of IL6 induced by disease- associated neurotoxin exposure in primary cultures. In these studies, we will determine if the JAK/STAT signal transduction pathway is activated by neurotoxins, and if once established, this pathway can be sustained in an IL6-dependent manner following cessation of exposure. In our second aim, we will use histologic and biochemical techniques to determine if the IL6/JAK/STAT pathway is activated and sustained in mice initially exposed to the disease-associated pesticide rotenone and determine if treatment with a pharmacologic inhibitor of JAK/STAT can normalize IL6 levels in mice during and following rotenone exposure. Understanding the basic cellular and molecular mechanisms of IL6 induction in astrocytes and in CNS cells subjected to neurotoxic stress may identify new pathways of interest for detecting and treating neuroinflammation occurring in association with normal aging and disease.