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.
Ma
Z
Z
Department of Cell Biology, University of Alabama, Birmingham, AL 35294, USA.
Qin
H
H
Benveniste
E N
EN
D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009687:Nuclear Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D050832:Interferon-Stimulated Gene Factor 3; D009687:Nuclear Proteins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D015534:Trans-Activators; D014157:Transcription Factors; C079868:gamma interferon activation factor; D016899:Interferon-beta; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9