The interferon-γ-induced GTPase, mGBP-2, inhibits tumor necrosis factor α (TNF-α) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-κB and rac protein

Sujata Balasubramanian, Meiyun Fan, Angela F. Messmer-Blust, Chuan Yang, Jill A. Trendel, Jonathan A. Jeyaratnam, Lawrence Pfeffer, Deborah J. Vestal

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)20054-20064
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number22
DOIs
StatePublished - Jun 3 2011

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rac GTP-Binding Proteins
GTP Phosphohydrolases
Matrix Metalloproteinase 9
Interferons
Tumor Necrosis Factor-alpha
Transcription
Chemical activation
Tumors
Assays
Cytokines
NIH 3T3 Cells
Oligonucleotide Probes
Chromatin Immunoprecipitation
Pathologic Processes
Fibroblasts
Chromatin
Neoplasms
Transcription Factors
Up-Regulation
Gels

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The interferon-γ-induced GTPase, mGBP-2, inhibits tumor necrosis factor α (TNF-α) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-κB and rac protein. / Balasubramanian, Sujata; Fan, Meiyun; Messmer-Blust, Angela F.; Yang, Chuan; Trendel, Jill A.; Jeyaratnam, Jonathan A.; Pfeffer, Lawrence; Vestal, Deborah J.

In: Journal of Biological Chemistry, Vol. 286, No. 22, 03.06.2011, p. 20054-20064.

Research output: Contribution to journalArticle

Balasubramanian, Sujata ; Fan, Meiyun ; Messmer-Blust, Angela F. ; Yang, Chuan ; Trendel, Jill A. ; Jeyaratnam, Jonathan A. ; Pfeffer, Lawrence ; Vestal, Deborah J. / The interferon-γ-induced GTPase, mGBP-2, inhibits tumor necrosis factor α (TNF-α) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-κB and rac protein. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 22. pp. 20054-20064.
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AU - Fan, Meiyun

AU - Messmer-Blust, Angela F.

AU - Yang, Chuan

AU - Trendel, Jill A.

AU - Jeyaratnam, Jonathan A.

AU - Pfeffer, Lawrence

AU - Vestal, Deborah J.

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AB - 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.

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