Transcriptional suppression of matrix metalloproteinase-9 gene expression by IFN-gamma and IFN-beta: critical role of STAT-1alpha.

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.