title: The interferon-stimulated gene factor 3 complex mediates the inhibitory effect of interferon-beta on matrix metalloproteinase-9 expression.
abstract: Matrix metalloproteinase-9 (MMP-9) displays a preference for a broad range of substrates including extracellular matrix proteins and cytokines. MMP-9 plays an important role in physiological processes, as well as in inflammatory diseases and numerous cancers. Interferon-beta is a pleiotropic cytokine with antiviral, antiproliferative and immunomodulatory activities. Interferon-beta positively regulates gene expression, predominantly through the Janus kinase-signal transducer and activator of transcription (STAT) pathway. However, little is known about the mechanisms used by interferon-beta to negatively regulate gene expression. In the present study, we show that interferon-beta inhibits MMP-9 gene expression at the transcriptional level. Using cell lines deficient in three components of the interferon-beta-activated interferon-stimulated gene factor 3 (ISGF3) complex (i.e. STAT-1, STAT-2 and interferon regulatory factor 9), the results of our study indicate that all three members are required for interferon-beta inhibition. Chromatin immunoprecipitation assays demonstrate that interferon-beta reduces recruitment of transcriptional activators and coactivators, such as nuclear factor kappa B p65, Sp1, CREB-binding protein and p300, to the MMP-9 promoter, and decreases the degree of histone acetylation at the MMP-9 promoter. This occurs in the absence of an association of the ISGF3 complex with the MMP-9 promoter. Taken together, these data define the role of interferon-beta and the ISGF3 members in suppressing MMP-9 gene expression.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, AL 53294-0005, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhao
authors.forename: Susan
authors.initials: S
authors.lastname: Nozell
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Ma
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D050832:Interferon-Stimulated Gene Factor 3 / Q000235:genetics / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D014443:Tyrosine; D016899:Interferon-beta; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate