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
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
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DOI：
10.1074/jbc.m111.249326
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发表时间：
2011-06-03
影响因子：
4.8
通讯作者：
Vestal, Deborah J.
中科院分区：
文献类型：
--
作者：
Balasubramanian, Sujata;Fan, Meiyun;Vestal, Deborah J.
基质金属蛋白酶-9（MMP-9）在许多正常和病理过程中起重要作用，包括肿瘤发生和转移过程中的血管生成开关。而TNF-α和其他细胞因子上调MMP-9的表达，干扰素（IFN）抑制MMP-9的表达。我们发现，IFN-γ处理或IFN诱导的GT3，mGBP-2的强制表达，通过抑制MMP-9转录，抑制NIH 3 T3成纤维细胞中TNF-α诱导的MMP-9表达。NF-κ B转录因子是TNF-α完全诱导MMP-9所必需的。IFN-γ和mGBP-2均抑制NF-κ B依赖性报告构建体的转录，表明mGBP-2通过抑制NF-κ B介导的转录来抑制MMP-9诱导。有趣的是，mGBP-2不抑制TNF-α诱导的I κ B α降解或p65/RelA易位到细胞核中。然而，mGBP-2抑制p65在凝胶迁移试验中与κ B寡核苷酸探针的结合和在染色质免疫沉淀试验中与MMP-9启动子的结合。此外，NIH 3 T3细胞中NF-κ B B的TNF-α激活依赖于Rac激活，如Rac 1的显性抑制形式抑制TNF-α诱导NF-κ B介导的转录所证明的。Rac在mGBP-2对NF-κ B的抑制作用中的作用通过以下发现进一步显示：mGBP-2抑制内源性Rac的TNF-α活化，并且组成型活化Rac可以在mGBP-2存在下恢复NF-κ B转录。这是IFN抑制MMP-9表达的细胞因子诱导的新机制。
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-alpha and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-gamma treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-alpha-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-kappa B transcription factor is required for full induction of MMP-9 by TNF-alpha. Both IFN-gamma and mGBP-2 inhibit the transcription of a NF-kappa B-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-kappa B-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-alpha-induced degradation of I kappa B alpha or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a kappa B oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-alpha activation of NF-kappa B in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-alpha induction of NF-kappa B-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-kappa B is further shown by the findings that mGBP-2 inhibits TNF-alpha activation of endogenous Rac and constitutively activate Rac can restore NF-kappa B transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.