Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states.
Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states.
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发表时间：
1998-03
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通讯作者：
Axel Pagenstecher;Anne K. Stalder;C. Kincaid;Steven D. Shapiro;lain L. Campbell
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作者：
Axel Pagenstecher;Anne K. Stalder;C. Kincaid;Steven D. Shapiro;lain L. Campbell
基质金属蛋白酶(MMPs)与中枢神经系统(CNS)炎症性疾病的发病机制有关，而基质金属蛋白酶(TIMPs)的组织抑制物--MMPs的主要内源性调节因子的作用尚不清楚。我们研究了正常小鼠、EAE小鼠和星形胶质细胞(胶质纤维酸性蛋白)靶向表达细胞因子白介素3(巨噬细胞/小胶质细胞脱髓鞘疾病)、白介素6(神经退行性疾病)或肿瘤坏死因子-α(淋巴细胞性脑脊髓炎)的转基因小鼠中枢神经系统中9个MMP基因和3个TIMP基因的时空表达模式。在正常小鼠中，基质金属蛋白酶MT1-MMP、基质分解酶3和明胶酶B低水平表达，而TIMP-2和TIMP-3分别在神经元和脉络丛高表达。在EAE和转基因小鼠中，观察到各种基质金属蛋白酶基因的显著诱导或上调，其模式在某种程度上是每种模型所特有的，并且有显著的TIMP-1诱导。原位定位实验显示，在炎性病变中仅限于白细胞和可能的小胶质细胞的MMP表达与在病变周围激活的星形胶质细胞中观察到的TIMP-1表达之间的二分性。这些发现表明，在正常和炎症状态下，中枢神经系统中单个MMP和TIMP基因的表达具有特定的空间和时间调节。在中枢神经系统炎症过程中，TIMP-1和基质金属蛋白酶表达的不同定位表明，这些基因产物之间的相互作用可能决定破坏性炎症灶的大小和分辨率。
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of inflammatory disorders of the central nervous system (CNS) whereas the contribution of the major endogenous counter-regulators of MMPs, the tissue inhibitors of the matrix metalloproteinases (TIMPs), is unclear. We investigated the temporal and spatial expression patterns in the CNS of nine MMP genes and three TIMP genes in normal mice, in mice with EAE, and in transgenic mice with astrocyte (glial fibrillary acidic protein)-targeted expression of the cytokines interleukin-3 (macrophage/microglial demyelinating disease), interleukin-6 (neurodegenerative disease), or tumor necrosis factor-alpha (lymphocytic encephalomyelitis). In normal mice, the MMPs MT1-MMP, stromelysin 3, and gelatinase B were expressed at low levels, whereas high expression of TIMP-2 and TIMP-3 was observed predominantly in neurons and in the choroid plexus, respectively. In EAE and the transgenic mice, significant induction or up-regulation of various MMP genes was observed, the pattern of which was somewhat specific for each of the models, and there was significant induction of TIMP-1. In situ localization experiments revealed a dichotomy between MMP expression that was restricted to leukocytes and possibly microglia within inflammatory lesions and TIMP-1 expression that was observed in activated astrocytes circumscribing the lesions. These findings demonstrate specific spatial and temporal regulation in the expression of individual MMP and TIMP genes in the CNS in normal and inflammatory states. The distinct localization of TIMP-1 and MMP expression during CNS inflammation suggests a dynamic state in which the interplay between these gene products may determine both the size and resolution of the destructive inflammatory focus.