Transcriptional suppression of matrix metalloproteinase-9 gene expression by IFN-gamma and IFN-beta: critical role of STAT-1alpha.
Transcriptional suppression of matrix metalloproteinase-9 gene expression by IFN-gamma and IFN-beta: critical role of STAT-1alpha.
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发表时间：
2001
影响因子：
4.4
通讯作者：
Z. Ma;H. Qin;E. Benveniste
中科院分区：
文献类型：
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作者：
Z. Ma;H. Qin;E. Benveniste
基质金属蛋白酶（MMP）是一类锌依赖性内肽酶家族，在细胞外基质的蛋白水解降解中起重要作用。92 kDa IV型胶原酶（MMP-9）的异常表达与恶性肿瘤的侵袭和血管生成过程以及CNS的炎性疾病有关。我们研究了用于治疗某些癌症和多发性硬化的细胞因子IFN-γ和IFN-β对人星形胶质瘤和纤维肉瘤细胞系以及原代星形胶质细胞中MMP-9表达的影响。我们的研究结果表明，IFN-γ和IFN-β显着抑制MMP-9的酶活性和蛋白质表达，诱导PMA和细胞因子TNF-α。IFN-γ和IFN-β对MMP-9表达的抑制作用与稳态MMP-9 mRNA水平降低和MMP-9启动子活性抑制相关。IFN-γ和IFN-β介导的MMP-9基因表达抑制依赖于转录因子STAT-1 α，因为IFN-γ和IFN-β不能抑制STAT-1 α缺陷的原代星形胶质细胞和人纤维肉瘤细胞中MMP-9的表达。重组人STAT-1 α成功恢复了IFN-γ和IFN-β对MMP-9基因表达的抑制作用。因此，这些数据证明了STAT-1 α在IFN-γ和IFN-β抑制MMP-9基因表达中的关键作用。
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play crucial roles in proteolytic degradation of the extracellular matrix. Aberrant expression of the 92-kDa type IV collagenase (MMP-9) is implicated in the invasion and angiogenesis process of malignant tumors and in inflammatory diseases of the CNS. We investigated the effects of IFN-gamma and IFN-beta, cytokines used for treating some cancers and multiple sclerosis, on MMP-9 expression in human astroglioma and fibrosarcoma cell lines and primary astrocytes. Our results demonstrate that IFN-gamma and IFN-beta significantly inhibit MMP-9 enzymatic activity and protein expression that is induced by PMA and the cytokine TNF-alpha. The inhibitory effects of IFN-gamma and IFN-beta on MMP-9 expression correlate with decreased steady state MMP-9 mRNA levels and suppression of MMP-9 promoter activity. IFN-gamma- and IFN-beta-mediated inhibition of MMP-9 gene expression is dependent on the transcription factor STAT-1alpha, since IFN-gamma and IFN-beta fail to suppress MMP-9 expression in STAT-1alpha-deficient primary astrocytes and human fibrosarcoma cells. Reconstitution of human STAT-1alpha successfully restores the inhibitory effects of IFN-gamma and IFN-beta on MMP-9 gene expression. Thus, these data demonstrate the critical role of STAT-1alpha in IFN-gamma and IFN-beta suppression of MMP-9 gene expression.