Cross A K, Woodroofe M N
Biomedical Research Centre, Division of Biomedical Sciences, Sheffield Hallam University, Sheffield, England.
Glia. 1999 Dec;28(3):183-9.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes, capable of degrading proteins found in the extracellular matrix. MMPs 2 and 9 are known to be produced by microglia, the resident macrophages of the central nervous system. The control of the secretion of these proteases and the activation of proenzymes by other proteases such as plasmin, as well as the balance between MMP secretion and the secretion of their natural inhibitors (TIMPs), have an important relevance in the pathogenesis of multiple sclerosis (MS). The in vitro control of MMPs 2 and 9, TIMPs 1 and 2, and urokinase-type plasminogen activator by microglia was examined in response to a panel of chemokines (chemotactic cytokines), using ELISA and zymography techniques. The chemokines MCP1, MIP1beta, RANTES, IL-8, and Fractalkine were all found significantly to increase the secretion of MMPs and TIMPs by a human foetal microglial cell line, CHME3, after 24 h stimulation. The chemokines tested, MCP1, MIP1beta, and Fractalkine, were also shown to increase MMP9 secretion by primary isolated rat brain microglia in vitro. MCP1, MIP1alpha/beta, and RANTES significantly decreased the secretion of uPA into culture supernatants in ELISA experiments. These findings suggest an important potential role for the involvement of chemokines in the breakdown of the blood-brain barrier and also the destruction of myelin basic protein in MS.
基质金属蛋白酶（MMPs）是一类锌依赖性酶，能够降解细胞外基质中的蛋白质。已知MMPs 2和9由小胶质细胞产生，小胶质细胞是中枢神经系统的常驻巨噬细胞。这些蛋白酶的分泌控制以及纤溶酶等其他蛋白酶对酶原的激活，以及MMP分泌与其天然抑制剂（TIMPs）分泌之间的平衡，在多发性硬化症（MS）的发病机制中具有重要意义。使用ELISA和酶谱技术，检测了小胶质细胞对一组趋化因子（趋化性细胞因子）的反应，对MMPs 2和9、TIMPs 1和2以及尿激酶型纤溶酶原激活剂的体外控制。在24小时刺激后，趋化因子MCP1、MIP1β、RANTES、IL-8和 fractalkine均被发现能显著增加人胎儿小胶质细胞系CHME3中MMPs和TIMPs的分泌。所测试的趋化因子MCP1、MIP1β和 fractalkine在体外也能增加原代分离的大鼠脑小胶质细胞中MMP9的分泌。在ELISA实验中，MCP1、MIP1α/β和RANTES显著降低了uPA向培养上清液中的分泌。这些发现表明趋化因子在血脑屏障破坏以及MS中髓鞘碱性蛋白破坏过程中可能发挥重要作用。
