Transcriptional Suppression of Matrix Metalloproteinase-9 Gene Expression by IFN-γ and IFN-β: Critical Role of STAT-1α

Ma, Zhendong; Qin, Hongwei; Benveniste, Etty N.

doi:10.4049/jimmunol.167.9.5150

Cited by 146 publications

(125 citation statements)

References 61 publications

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“…To gain insight in these early circuits, we studied the expression and the activation of STAT-1, which is in an intracellular target of IL-12-induced biologic activities (19,20) and negatively regulates MMP9 transcription (83). In our experimental conditions, we observe that STAT-1 is expressed and tyrosine phosphorylated in stimulated PBMC and CD4 ϩ cells regardless of the presence of ECs but not in stimulated CD8 ϩ , corroborating the morphologic observations discussed above.…”

Section: Discussionsupporting

confidence: 83%

IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

Mitola¹,

Strasly²,

Prato³

et al. 2003

The Journal of Immunology

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IL-12 is key cytokine in innate immunity and participates in tumor rejection by stimulating an IFN-γ-mediated response characterized by CD8+ mediated-cytotoxicity, inhibition of angiogenesis, and vascular injury. We previously demonstrated that activated lymphocytes stimulated with IL-12 induced an angiostatic program in cocultured vascular endothelial cells. In this study, we have extended this observation showing that a reciprocal modulation of cellular responses occurs. Actually, the presence of endothelial cells enhanced the inhibitory effect of IL-12 on metalloproteinase-9 expression in activated PBMC as well as their ability to transmigrate across an extracellular matrix. IL-12 triggered intracellular signaling, as indicated by STAT-1 activation, appeared to mainly operative in activated CD4 + cells challenged with IL-12, but it was also initiated in CD8+ lymphocytes in the presence of endothelial cells. On the other hand, stimulated PBMC reduced the expression and the activity of metalloproteinase-9, up-regulated that of tissue inhibitor metalloproteinase-1, and stimulated the STAT-1 pathway in cocultured endothelial cells. We used neutralizing Abs to show that the IFN-inducible protein 10 (CXCL10) and monokine-induced by IFN-γ (CXCL9) chemokines produced by both PBMC and endothelial cells are pivotal in inducing these effects. Altogether these results suggest the existence of an IL-12-regulated circuit between endothelium and lymphocytes resulting in a shift of proteolytic homeostasis at site of tissue injury.

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Section: Discussionsupporting

confidence: 83%

IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

Mitola¹,

Strasly²,

Prato³

et al. 2003

The Journal of Immunology

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“…In contrast to receptor-activated Smads, Smad7 binds stably to TGF-b receptors and interferes with ligandinduced phosphorylation of Smad2 and Smad3 (Hayashi et al, 1997; Nakao et al, 1997). It has been shown that IFN-g inhibits the TGF-b signaling pathway through the induction of Smad7 or competition between Smads and STAT1 for limited amounts of the shared cellular coactivators p300/CBP (Ghosh et al, 2001;Ma et al, 2001). In our experiments, IFN-g inhibited the effects of TGF-b-dependent GCTM-1 invasion (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model

et al. 2003

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We reconstituted a three-dimensional gastric carcinoma model similar to invasive gastric carcinoma tissue. This model consists of a human gastric carcinoma cell line, GCTM-1, a human fibroblast cell line, TIG-1-20, and transforming growth factor-b (TGF-b)-containing type I collagen gel. Using this model, we were able to observe the growth of the two cell types, especially carcinoma cell invasive growth, in real time for more than 30 days. TGFb and TIG-1-20 were essential for GCTM-1 invasive growth and proliferation, respectively. TGF-b induced the enhanced expression of matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA) in GCTM-1 at both the protein and enzymatic activity levels. The TGF-b-induced invasion of GCTM-1 was inhibited by MMP9-or uPA-antisense (AS) oligonucleotide transfection to GCTM-1. When exogenous interferon-c (IFN-c) was added to this model, TGF-bdependent GCTM-1 invasion was significantly inhibited, concomitant with the decreased expression of MMP9 and uPA. The intracellular signal transduction of Smad was examined to analyse the mechanism of the inhibitory effect of IFN-c. TGF-b accelerated the phosphorylation of Smad2/3 and nuclear translocation of the Smad2/3-Smad4 complex in GCTM-1, but these TGF-b-induced effects were significantly inhibited by IFN-c-induced Smad7 expression. When GCTM-1 was cotransfected with AS oligonucleotide of Smad2 and Smad3, the TGFb-induced invasion of GCTM-1 disappeared. In addition, the inhibitory effect of IFN-c on TGF-b-dependent GCTM-1 invasion vanished by the AS oligonucleotide of Smad7 transfection. These results indicate that IFN-c inhibits TGF-b-dependent GCTM-1 invasion through cross-talk in the Smad pathway. IFN-c may be a new therapeutic tool for TGF-b-expressed invasive carcinomas.

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“…Also, IFN was shown to be able to down-regulate C/EBPα IFN was shown to down-regulate the IL-1 gene in murine macrophages but it was unable to do so in Stat1 -/-animals (De Boer et al, 2001). Furthermore, IFN suppresses MMP-9 via Stat1 (Ma et al, 2001b) and this appears to be due to sequestration of CBP/p300 such that this coactivator is not available for transcription of the MMP-9 gene (Ma et al, 2005).…”

Section: Effect Of Ifn On Binding Of Stat1 and Stat3 In The Intact Numentioning

confidence: 99%

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

Schaefer

Unterberger

Frankenberger

et al. 2009

Molecular Immunology

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Transcriptional Suppression of Matrix Metalloproteinase-9 Gene Expression by IFN-γ and IFN-β: Critical Role of STAT-1α

Cited by 146 publications

References 61 publications

IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

Interferon-γ suppresses transforming growth factor-β-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

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