title: The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein.
abstract: Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-κB transcription factor is required for full induction of MMP-9 by TNF-α. Both IFN-γ and mGBP-2 inhibit the transcription of a NF-κB-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-κB-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-α-induced degradation of IκBα or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a κB oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-α activation of NF-κB in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-α induction of NF-κB-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-κB is further shown by the findings that mGBP-2 inhibits TNF-α activation of endogenous Rac and constitutively activate Rac can restore NF-κB transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.forename: Angela F
authors.initials: AF
authors.lastname: Messmer-Blust
authors.forename: Chuan H
authors.initials: CH
authors.lastname: Yang
authors.forename: Jill A
authors.initials: JA
authors.lastname: Trendel
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Jeyaratnam
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Vestal
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D041681:NIH 3T3 Cells; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D000998:Antiviral Agents; D020672:I-kappa B Proteins; D009479:Neuropeptides; C000606205:Nfkbia protein, mouse; C484602:Rac1 protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D019204:GTP-Binding Proteins; C452200:Gbp2 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein