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-γ and IFN-β, 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-γ and IFN-γ significantly inhibit MMP-9 enzymatic activity and protein expression that is induced by PMA and the cytokine TNF-α. The inhibitory effects of IFN-γ and IFN-β on MMP-9 expression correlate with decreased steady state MMP-9 mRNA levels and suppression of MMP-9 promoter activity. IFN-γ- and IFN-β-mediated inhibition of MMP-9 gene expression is dependent on the transcription factor STAT.1α, since IFN-γ and IFN-β fail to suppress MMP-9 expression in STAT-1α-deficient primary astrocytes and human fibrosarcoma cells. Reconstitution of human STAT.1α successfully restores the inhibitory effects of IFN-γ and IFN-β on MMP-9 gene expression. Thus, these data demonstrate the critical role of STAT-la in IFN-β and IFN-β suppression of MMP-9 gene expression.