Schäbitz Wolf-Rüdiger, Krüger Carola, Pitzer Claudia, Weber Daniela, Laage Rico, Gassler Nikolaus, Aronowski Jaroslaw, Mier Walter, Kirsch Friederike, Dittgen Tanjew, Bach Alfred, Sommer Clemens, Schneider Armin
Department of Neurology, University of Münster, Münster, Germany.
J Cereb Blood Flow Metab. 2008 Jan;28(1):29-43. doi: 10.1038/sj.jcbfm.9600496. Epub 2007 Apr 25.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine responsible for the proliferation, differentiation, and maturation of cells of the myeloid lineage, which was cloned more than 20 years ago. Here we uncovered a novel function of GM-CSF in the central nervous system (CNS). We identified the GM-CSF alpha-receptor as an upregulated gene in a screen for ischemia-induced genes in the cortex. This receptor is broadly expressed on neurons throughout the brain together with its ligand and induced by ischemic insults. In primary cortical neurons and human neuroblastoma cells, GM-CSF counteracts programmed cell death and induces BCL-2 and BCL-Xl expression in a dose- and time-dependent manner. Of the signaling pathways studied, GM-CSF most prominently induced the PI3K-Akt pathway, and inhibition of Akt strongly decreased antiapoptotic activity. Intravenously given GM-CSF passes the blood-brain barrier, and decreases infarct damage in two different experimental stroke models (middle cerebral artery occlusion (MCAO), and combined common carotid/distal MCA occlusion) concomitant with induction of BCL-Xl expression. Thus, GM-CSF acts as a neuroprotective protein in the CNS. This finding is remarkably reminiscent of the recently discovered functionality of two other hematopoietic factors, erythropoietin and granulocyte colony-stimulating factor in the CNS. The identification of a third hematopoietic factor acting as a neurotrophic factor in the CNS suggests a common principle in the functional evolution of these factors. Clinically, GM-CSF now broadens the repertoire of hematopoietic factors available as novel drug candidates for stroke and neurodegenerative diseases.
粒细胞巨噬细胞集落刺激因子（GM-CSF）是一种造血细胞因子，负责髓系谱系细胞的增殖、分化和成熟，该因子于20多年前被克隆。在此，我们发现了GM-CSF在中枢神经系统（CNS）中的一种新功能。我们在皮质缺血诱导基因的筛选中，将GM-CSFα受体鉴定为上调基因。该受体与其配体一起在全脑的神经元上广泛表达，并由缺血性损伤诱导产生。在原代皮质神经元和人神经母细胞瘤细胞中，GM-CSF可对抗程序性细胞死亡，并以剂量和时间依赖性方式诱导BCL-2和BCL-Xl表达。在所研究的信号通路中，GM-CSF最显著地诱导PI3K-Akt通路，抑制Akt可强烈降低抗凋亡活性。静脉注射GM-CSF可穿过血脑屏障，并在两种不同的实验性中风模型（大脑中动脉闭塞（MCAO）以及颈总动脉/大脑中动脉远端联合闭塞）中减少梗死损伤，同时诱导BCL-Xl表达。因此，GM-CSF在中枢神经系统中作为一种神经保护蛋白发挥作用。这一发现明显让人联想到最近在中枢神经系统中发现的另外两种造血因子——促红细胞生成素和粒细胞集落刺激因子的功能。在中枢神经系统中鉴定出第三种作为神经营养因子的造血因子，提示了这些因子在功能进化中的共同原则。临床上，GM-CSF现在拓宽了作为中风和神经退行性疾病新型候选药物的造血因子种类。
