Modulation of monocytes matrix metalloproteinase-2, MT1-MMP and TIMP-2 by interferon-γ and -β: implications to multiple sclerosis

Galboiz, Yanina; Shapiro, Sarah; Lahat, Nitza; Miller, David H.

doi:10.1016/s0165-5728(02)00266-7

Cited by 28 publications

(22 citation statements)

References 52 publications

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“…Among these cytokines, IFNb is used clinically to treat patients with multiple sclerosis (MS). 48 It has been proposed that the IFNb-mediated downregulation of MMP2 expression in monocytes contributes to the beneficial effect of IFNb in MS. 49 Treating tumor cells with IFNb decreases MMP2 expression, which suppresses tumor metastasis. 50 De novo protein synthesis is required for optimal interferonmediated inhibition of MMP2 expression.…”

Section: Discussionmentioning

confidence: 99%

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

et al. 2014

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Promyelocytic leukemia protein (PML) is emerging as an important tumor suppressor. Its expression is lost during the progression of several types of cancer, including lung cancer. The EGF receptor (EGFR), a membrane-bound receptor tyrosine kinase, transduces intracellular signals responsible for cell proliferation, differentiation and migration. EGFR activity is frequently abnormally upregulated in lung adenocarcinoma (LAC) and thus is considered to be a driving oncogene for LAC. EGFR translocates into the nucleus and transcriptionally activates genes, such as CCND1, that promote cell growth. Recently, we demonstrated that PML interacted with nuclear EGFR (nEGFR) and suppressed the nEGFR-mediated transcriptional activation of CCND1 in lung cancer cells, thereby restraining cell growth. When we further investigated the interplay between PML and EGFR in lung cancer metastasis, we found that the matrix metalloprotease-2 gene (MMP2) was a novel nEGFR target gene and was repressed by PML. We provide evidence that nEGFR bound to the AT-rich sequence (ATRS) in the MMP2 promoter and enhanced its transcriptional activity. In addition, we demonstrated that PML repressed nEGFR-induced MMP2 transcription and reduced cell invasion. PML was recruited by nEGFR to the MMP2 promoter where it reduced histone acetylation, leading to the transcriptional repression of MMP2. Finally, we demonstrated that PML upregulation by interferon-b (IFNb) in lung cancer cells decreased MMP2 expression and cell invasion. Together, our results suggested that IFNb induced PML to inhibit lung cancer metastasis by repressing the nEGFR-mediated transcriptional activation of MMP2.

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Section: Discussionmentioning

confidence: 99%

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

et al. 2014

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“…Selective or differential cell trafficking can potentially introduce additional variability in array data because it is difficult to separate the gene expression level changes that are caused by changes in the transcription rates from those caused by changes in cell numbers. Therefore, the genomic changes in monocytes, which may be an important target cell type for IFN-␤ immunomodulation, were not measured (31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Genomic Effects of IFN-β in Multiple Sclerosis Patients

Weinstock‐Guttman

Badgett²,

Patrick

et al. 2003

The Journal of Immunology

112

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The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-β-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 μg of IFN-β-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN-β-1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1–4 h of IFN-β treatment. The mRNAs for several genes involved in IFN-β signaling, such as IFN-α/β receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9–27), IFN-induced transmembrane protein 2 (1–8D), β2-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN-β treatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy.

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“…Next, stabilizing functions of endothelial tight junctions on cultured cells have been demonstrated (18). In addition, the expression of matrix metalloproteinases has been shown to be inhibited by IFN-␤ (19). However, despite the efforts made to elucidate the subject, several reports concerning the effects of IFN-␤ on APCs (macrophages) and on T cells are contradictory, as both anti-and proinflammatory properties have been suggested.…”

Section: Ifn-␤ Inhibits T Cell Activation Capacity Of Central Nervousmentioning

confidence: 99%

IFN-β Inhibits T Cell Activation Capacity of Central Nervous System APCs

Teige

Liu

Issazadeh‐Navikas

2006

The Journal of Immunology

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We have previously investigated the physiological effects of IFN-β on chronic CNS inflammation and shown that IFN-β−/− mice develop a more severe experimental autoimmune encephalomyelitis than their IFN-β+/− littermates. This result was shown to be associated with a higher activation state of the glial cells and a higher T cell cytokine production in the CNS. Because this state suggested a down-regulatory effect of IFN-β on CNS-specific APCs, these results were investigated further. We report that IFN-β pretreatment of astrocytes and microglia (glial cells) indeed down-modulate their capacity to activate autoreactive Th1 cells. First, we investigated the intrinsic ability of glial cells as APCs and report that glial cells prevent autoreactive Th1 cells expansion while maintaining Ag-specific T cell effector functions. However, when the glial cells are treated with IFN-β before coculture with T cells, the effector functions of T cells are impaired as IFN-γ, TNF-α, and NO productions are decreased. Induction of the T cell activation marker, CD25 is also reduced. This suppression of T cell response is cell-cell dependent, but it is not dependent on a decrease in glial expression of MHC class II or costimulatory molecules. We propose that IFN-β might exert its beneficial effects mainly by reducing the Ag-presenting capacity of CNS-specific APCs, which in turn inhibits the effector functions of encephalitogenic T cells. This affect is of importance because activation of encephalitogenic T cells within the CNS is a prerequisite for the development of a chronic progressive CNS inflammation.

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Modulation of monocytes matrix metalloproteinase-2, MT1-MMP and TIMP-2 by interferon-γ and -β: implications to multiple sclerosis

Cited by 28 publications

References 52 publications

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

Genomic Effects of IFN-β in Multiple Sclerosis Patients

IFN-β Inhibits T Cell Activation Capacity of Central Nervous System APCs

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