Thornton Peter, Pinteaux Emmanuel, Allan Stuart M, Rothwell Nancy J
Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Mol Cell Neurosci. 2008 Jan;37(1):135-42. doi: 10.1016/j.mcn.2007.09.002. Epub 2007 Sep 12.
Matrix metalloproteinases (MMPs) are endopeptidases known to mediate acute neuronal injury, but it is unclear whether these proteases are induced by the primary insult or by inflammation associated with injury. We have reported recently that interleukin-1 (IL-1) induces neurotoxicity by an astrocyte-dependent mechanism. The aim of the present study was to test the hypothesis that MMPs mediate IL-1 neurotoxicity in rat, glial-neuronal cocultures. IL-1beta induced the release of astrocytic MMP-9 in cocultures, whilst an antagonist of MMP-9 inhibited IL-1beta-induced neuronal death. Urokinase plasminogen activator (uPA) was constitutively expressed on neuronal membrane fractions, and amiloride (an antagonist of uPA) or plasminogen activator inhibitor (PAI)-1 significantly reduced IL-1beta-induced neurotoxicity. Thus, neuronal uPA contributes to IL-1 neurotoxicity, and may be responsible for activating MMP-9 released from IL-1-primed astrocytes. In summary, IL-1-induced neurotoxicity is dependent on extracellular protease activity, and these mechanisms may contribute to neuronal cell death in CNS diseases.
基质金属蛋白酶（MMPs）是已知可介导急性神经元损伤的内肽酶，但尚不清楚这些蛋白酶是由原发性损伤诱导还是由与损伤相关的炎症诱导。我们最近报道白细胞介素-1（IL-1）通过星形胶质细胞依赖的机制诱导神经毒性。本研究的目的是检验MMPs介导大鼠神经胶质-神经元共培养物中IL-1神经毒性这一假说。IL-1β在共培养物中诱导星形胶质细胞MMP-9的释放，而MMP-9拮抗剂抑制IL-1β诱导的神经元死亡。尿激酶型纤溶酶原激活剂（uPA）在神经元膜组分上组成性表达，而阿米洛利（uPA拮抗剂）或纤溶酶原激活剂抑制剂（PAI）-1显著降低IL-1β诱导的神经毒性。因此，神经元uPA促成IL-1神经毒性，并且可能负责激活从IL-1预处理的星形胶质细胞释放的MMP-9。总之，IL-1诱导的神经毒性依赖于细胞外蛋白酶活性，并且这些机制可能促成中枢神经系统疾病中的神经元细胞死亡。
