Interferons inhibit tumor necrosis factor-alpha-mediated matrix metalloproteinase-9 activation via interferon regulatory factor-1 binding competition with NF-kappa B.
Enhanced expression of matrix metalloproteinase-9 (MMP-9) correlates with invasion during tumor progression. Interferons (IFNs) inhibit MMP-9 activation in response to tumor necrosis factor-alpha (TNF-alpha), and the latter activates the MMP-9 gene through NF-kappaB. Understanding the molecular basis for MMP-9 inhibition may provide tools to control cell invasion. The data reported here show the critical role of interferon regulatory factor-1 (IRF1) in the inhibition of MMP-9. (i) IFN treatment suppresses TNF-alpha-induced MMP-9 reporter activity in STAT1(+/+) cells but not in STAT1(-/-) cells. (ii) IRF1 transfection blocks TNF-alpha-mediated MMP-9 activation. (iii) IFNs phosphorylate STAT1 and induce IRF1 but do not affect Ikappa-B degradation nor NF-kappaB nuclear translocation. (iv) Nuclear NF-kappaB (p50/p65) and IRF1, but not STAT1, bind to the MMP-9 promoter region containing an IFN-responsive-like element overlapping the NF-kappaB-binding site. (v) Recombinant IRF1, although unable to bind to an NF-kappaB consensus sequence, competes with NF-kappaB proteins for binding to the MMP-9 promoter. (vi) Conversely recombinant p50/p65 proteins reduce IRF1-DNA binding. (vii) In cells cotransfected with IRF1 and/or p65 expression vectors, an excess of IRF1 reduces MMP-9 reporter activity, whereas an excess of p65 blocks the inhibitory effect of IFN-gamma. Thus, in contrast to the known synergism between IRF1 and NF-kappaB, our data identify a novel role for IRF1 as a competitive inhibitor of NF-kappaB binding to the particular MMP-9 promoter context.
Sancéau
Josiane
J
Unité 365 INSERM, Section de Recherche, Institut Curie, 75248 Paris Cedex 05, France.
Boyd
Douglas D
DD
Seiki
Motoharu
M
Bauvois
Brigitte
B
D001483:Base Sequence; D001667:Binding, Competitive; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007372:Interferons / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; D020780:Matrix Metalloproteinase 9