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Results for “Matrix Metalloproteinases, Secreted”

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PubMed1998

Effect of glucose on matrix metalloproteinase activity in mesangial cells.

Mesangial cells are known to secrete matrix metalloproteinases (MMPs). These enzymes play a major role in the degradation and remodelling of extracellular matrix, and alterations in their activity may contribute to the mesangium enlargement of diabetic nephropathy. MMPs are secreted as latent forms which are cleaved in the pericellular environment to form active enzymes. In this study, we used a biosynthetically labelled matrix as substrate and conditioned medium obtained from mesangial cells, as a source of enzymes to investigate the effect of a high glucose concentration on degradative capacity. Inhibitor studies showed that MMPs were responsible for 72.2% of the degradation. A high glucose concentration caused a significant reduction in matrix degradation (low glucose 33.5 +/- 5.6%, high glucose 24.2 +/- 4.8%). Addition of aminophenyl mercuric acetate to activate latent MMPs increased matrix degradation by 2.3-fold in both low- and high-glucose media, but the decreased degradation caused by a high glucose concentration was still apparent. Activation with plasmin also increased matrix degradation and abolished the effect of the high glucose concentration. Gelatin zymography showed that mesangial cells grown at a low glucose concentration secreted both 72- and 92-kD gelatinases; however, at high glucose concentrations the 92-kD gelatinase was no longer apparent. These results suggest that a high glucose concentration causes a reduction in the amount of MMPs secreted by the mesangial cells. This reduction may contribute to the mesangium enlargement of diabetic nephropathy.

Cells, Cultured↗

PubMed2006

Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways.

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Several recent studies have reported that ionizing radiation (IR) enhances the invasion of tumor cells, but the mechanisms for this effect are not well understood. In this study, we investigated the possible signaling mechanisms involved in IR-induced invasion of glioma cells. IR increased the matrix metalloproteinase (MMP)-2 promoter activity, mRNA transcription, and protein secretion along with the invasiveness of glioma cells lacking functional PTEN (U87, U251, U373, and C6) but not those harboring wild-type (WT)-PTEN (LN18 and LN428). IR activated phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin, and blockade of these kinases by specific inhibitors (LY294002, Akt inhibitor IV, and rapamycin, respectively) and transfection of dominant-negative (DN) mutants (DN-p85 and DN-Akt) or WT-PTEN suppressed the IR-induced MMP-2 secretion in U251 and U373 cells. In addition, inhibitors of epidermal growth factor receptor (EGFR; AG490 and AG1478), Src (PP2), and p38 (SB203580), EGFR neutralizing antibody, and transfection of DN-Src and DN-p38 significantly blocked IR-induced Akt phosphorylation and MMP-2 secretion. IR-induced activation of EGFR was suppressed by PP2, whereas LY294002 and SB203580 did not affect the activations of p38 and PI3K, respectively. Finally, these kinase inhibitors significantly reduced the IR-induced invasiveness of these cells on Matrigel. Taken together, our findings suggest that IR induces Src-dependent EGFR activation, which triggers the p38/Akt and PI3K/Akt signaling pathways, leading to increased MMP-2 expression and heightened invasiveness of PTEN mutant glioma cells.

Animals↗

PubMed2000

Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that directly control numerous genes of lipid metabolism by binding to response elements in the promoter. It has recently been proposed that PPARgamma may also regulate genes for proinflammatory proteins, not through PPRE binding but by interaction with transcription factors AP-1, STAT, and NF-kappaB. Recent studies with cultured human monocytes, however, have failed to observe an inhibitory effect of PPARgamma agonists on induced expression of TNFalpha and IL-6, genes known to be controlled by AP-1, STAT, and NF-kappaB. In a similar fashion, we show here that PPARalpha (fenofibrate) or PPARgamma (rosiglitazone) agonists failed to modulate LPS-induced secretion of IL-8 in THP-1 cells. When we made parallel observations on another gene, matrix metalloproteinase 9 (MMP-9), we were surprised to find profound downregulation of LPS-induced secretion by both PPARalpha or PPARgamma agonists. These findings suggest that PPAR may regulate only a subset of the proinflammatory genes controlled by AP-1, STAT, and NF-kappaB. Effects of PPARs on MMP-9 may account for the beneficial effect of PPAR agonists in animal models of atherosclerosis.

Cell Nucleus↗

PubMed2004

Interaction of cocultured decidual endothelial cells and cytotrophoblasts in preeclampsia.

Disturbed cell-cell communication between trophoblasts and the maternal endothelium may be responsible for the deficient endovascular invasion seen in preeclampsia. In vitro studies have been hampered by lack of suitable models to directly examine interactions between these cell types. Using a bilayer coculture model, we examined the effect of decidual endothelial cells on matrix metalloproteinase secretion and the migration of cytotrophoblasts from preeclamptic pregnancies. Cells were incubated on semipermeable membranes in 20% or 2% O(2) with or without the tumor promoter phorbol 12-myristate 13-acetate, which activates matrix metalloproteinase-2 and -9 in endothelial cells. Cytotrophoblasts from preeclamptic pregnancies secreted significantly less matrix metalloproteinase-2 and -9 than their normal counterparts. Although decidual endothelial cells downregulated cytotrophoblast migration in normal pregnancy, this was not observed in cocultures with cytotrophoblasts from preeclamptic pregnancies. In addition, cytotrophoblasts from preeclamptic pregnancies altered phorbol myristate acetate-induced activation of endothelial matrix metalloproteinases. Hypoxia increased cytotrophoblast migration when cells were incubated alone but not in coculture with decidual endothelial cells due to increased adhesion between the two cell types. These results suggest dysfunctional interactive regulation of migration and matrix metalloproteinase secretion in preeclampsia that could result in abnormal endovascular trophoblast invasion of the maternal vasculature.

Cell Communication↗

PubMed2006

Inhibition of matrix metalloproteinase-2 secretion and invasion by human ovarian cancer cell line SK-OV-3 with lysine, proline, arginine, ascorbic acid and green tea extract.

AIMS: Based on the poor prognosis associated with ovarian cancer and reported anticancer properties of specific nutrients, we investigated the effect of a nutrient mixture (NM) containing lysine, proline, arginine, ascorbic acid and epigallocatechin gallate on human ovarian cancer cells SK-OV-3 by measuring: cell proliferation, modulation of matrix metalloproteinase (MMP)-2 and -9 expression, and cancer cell invasive potential. METHODS: Cell proliferation was evaluated by MTT assay, MMP activity by gelatinase zymography, and invasion through Matrigel. RESULTS: Human ovarian cancer cell growth was not significantly affected by the NM. Zymography demonstrated inhibition of MMP-2 secretion in a dose-dependent fashion with virtual total inhibition at 50 microg/mL NM concentration. Invasion of human ovarian cancer cells through Matrigel decreased in a dose-dependent fashion, with 90% inhibition at 500 microg/mL NM and 100% inhibition at 1000 microg/mL NM (P < 0.0001). CONCLUSION: The combination of lysine, proline, arginine, ascorbic acid and green tea extract tested inhibited critical steps in cancer development and spread, such as MMP expression and invasion, indicating its potential as a treatment modality against ovarian cancer.

Amino Acids↗

PubMed2001

Secretion of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases into follicular fluid during follicle development in equine ovaries.

Extensive tissue remodelling is required in equine ovaries for follicle growth and development and also migration of the follicle to the ovulatory fossa, where ovulation occurs. The mechanisms for these processes are largely unexplored. Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) are important for control of breakdown of extracellular matrix during tissue remodelling. The aims of this study were to determine the pattern and sites of secretion of the gelatinases MMP-2 and -9 and TIMPs into follicular fluid during follicle development in mare ovaries. The predominant gelatinase detected in follicular fluid was MMP-2, which was present in similar amounts throughout follicular development, as demonstrated by zymography. MMP-9 was also present in follicular fluid and secretion increased significantly (P < 0.05) with development of follicles from < 10 mm to 11-20 mm in diameter. Follicular fluid also contained TIMP-1, TIMP-2, unglycosylated and glycosylated TIMP-3, and TIMP-4, as shown by reverse zymography. The abundance of TIMPs remained largely unchanged during follicle development. MMP-2 and -9 were localized by immunohistochemistry to stromal cells and granulosa and theca cells. TIMP-1, -2, -3 and -4 were present in granulosa and theca cells of the follicle and in stromal cells and also associated with extracellular matrix of the ovarian stromal tissue. The MMPs and TIMPs are likely to be involved in the regulation of the breakdown of extracellular matrix during tissue remodelling for follicle development and migration to the ovulation fossa in mares.

Animals↗

PubMed2005

Secretion of matrix metalloproteinase-9 by macrophages, in vitro, in response to Helicobacter pylori.

We have previously shown that matrix metalloproteinase-9 (MMP-9) activity is greatly enhanced within the active chronic inflammation of Helicobacter pylori infected individuals, of which a major fraction derives from macrophages in the tissue. Here, we have investigated the ability of macrophages to secrete MMPs in response to H. pylori. Human macrophages secrete MMP-9 in response to live and inactivated H. pylori, as well as to specific bacterial products. Protein kinase C, phosphatiolylinositol 3-kinase and calcium uptake channels all play a role in MMP-9 secretion, whereas neither tumour necrosis factor alpha, interleukin-8, nor interleukin-1beta autocrine stimulation appear to contribute. We conclude that human macrophages have the ability to react directly against several H. pylori derived factors, utilising several signalling pathways.

Base Sequence↗

PubMed1999

Secretion of matrix metalloproteinase-2, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases into the intrauterine compartments during early pregnancy.

Matrix metalloproteinases (MMPs) are important enzymes in tissue remodelling, a key event for the development of the fetal membranes and placenta and establishing the feto-maternal interface during early pregnancy. This study has examined the secretion of the gelatinases, MMP-2 (72 kDa) and MMP-9 (92 kDa), and the endogenous tissue inhibitors of metalloproteinases (TIMPs) into extra-embryonic coelomic and amniotic fluids, the two principal intra-uterine compartments of the first trimester, and compared them to amniotic fluid collected later in gestation. In extra-embryonic coelomic fluid, gelatin zymography demonstrated that MMP-2 (72 kDa) was the predominant gelatinase, with some MMP-9 present. A broad range of TIMPs corresponding to TIMP-1 and TIMP-2, glycosylated and unglycosylated TIMP-3 and TIMP-4 was detected in this compartment by reverse zymography and immunoblot analyses. There was little gelatinase or TIMP activity in amniotic fluid in the first trimester. In amniotic fluid from the second trimester after fusion of the membranes obliterating the extra-embryonic coelom, and at term elective caesarean section, MMP-2 is the predominant gelatinase present, with a broad spectrum of TIMPs. These findings demonstrate that predominantly MMP-2 and also MMP-9, regulated by a range of TIMPs, are involved in intra-uterine tissue remodelling during the establishment of pregnancy.

Adult↗

PubMedDate not supplied

Examination gloves affect secretion of matrix metalloproteinases and their inhibitors from human abdominal skin fibroblasts.

Overexpression of matrix metalloproteinases (MMPs) has been observed in chronic, compared to acute, wounds and altered levels might impair healing. During treatment of wounds, examination gloves are routinely used, and the wound environment thus gets exposed to gloves. The aim of this study was to characterize secretion of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in cultured fibroblasts with or without exposure to gloves. Cultures were exposed to glove washings from powdered or powder-free latex examination gloves and compared to untreated controls. MMP-1, -2, -3, -9 and their inhibitors TIMP-1 and -2 were assayed in conditioned media. Cells exposed to gloves reduced their release of MMP-1, -2, and -3 with no differences between the manufacturers of the gloves. The inhibitor TIMP-1 was reduced to 10-15% of untreated control values (p < 0.001), being less affected by the powder-free than by the powdered glove (p < 0.05). MMP-9 and TIMP-2 were not significantly altered. We therefore conclude that secretion of MMPs and TIMPs from cultured fibroblasts were affected by glove washings. Powdered and powder-free gloves had similar effects, except for a less pronounced reduction of TIMP-1 production by the powder-free glove. Examination gloves might therefore affect wound healing, with the least pronounced effect observed using the powder-free glove.

Cells, Cultured↗

PubMed2006

Regulation of angiogenesis and invasion by human Pituitary tumor transforming gene (PTTG) through increased expression and secretion of matrix metalloproteinase-2 (MMP-2).

BACKGROUND: Pituitary tumor transforming gene (PTTG) is a novel oncogene that is expressed at higher level in most of the tumors analyzed to date compared to normal tissues. Existence of a relationship between PTTG levels and tumor angiogenesis and metastasis has been reported. However, the mechanisms by which PTTG achieve these functions remain unknown. In the present study, we investigated the effect of overexpression of PTTG on secretion and expression of metastasis-related metalloproteinase-2 (MMP-2) in HEK293 cells, cell migration, invasion and tubule formation. RESULTS: Transient or stable transfection of HEK293 cells with PTTG cDNA showed a significant increase in secretion and expression of MMP-2 measured by zymography, reverse transcriptase (RT/PCR), ELISA, and MMP-2 gene promoter activity. Furthermore, in our studies, we showed that tumor developed in nude mice on injection of HEK293 cells that constitutively express PTTG expressed high levels of both MMP-2 mRNA and protein, and MMP-2 activity. Conditioned medium collected from the HEK293 cells overexpressing PTTG showed a significant increase in cell migration, invasion and tubule formation of human umbilical vein endothelial cells (HUVEC). Pretreatment of conditioned medium with MMP-2-specific antibody significantly decreased these effects, suggesting that PTTG may contribute to tumor angiogenesis and metastasis via activation of proteolysis and increase in invasion through modulation of MMP-2 activity and expression. CONCLUSION: Our results provide novel information that PTTG contributes to cell migration, invasion and angiogenesis by induction of MMP-2 secretion and expression. Furthermore, we showed that tumors developed in nude mice on injection of HEK293 cells that constitutively express PTTG induce expression of MMP-2 and significantly increase its functional activity, suggesting a relationship between PTTG levels and MMP-2 which may play a critical role in regulation of tumor growth, angiogenesis and metastasis. Blocking of function of PTTG or down regulation of its expression in tumors may result in suppression of tumor growth and metastasis, through the down regulation of MMP-2 expression and activity. To our knowledge, this study is the first study demonstrating the modulation of MMP-2 expression and biological activity by PTTG.

Animals↗

PubMed2002

Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase.

Matrix metalloproteinases (MMP) are involved in the pathophysiology of brain injury. We recently showed that knockout mice deficient in MMP-9 expression were protected against traumatic brain injury. However, the cellular sources of MMP activity after trauma remain to be fully defined. In this study, we investigated the hypothesis that resident brain cells secrete MMP after mechanical trauma injury in vitro, and mitogen-activated protein (MAP) kinase signal transduction pathways are involved in this response. Rat primary cortical neurons, astrocytes, and co-cultures were subjected to needle scratch mechanical injury, and levels of MMP-2 and MMP-9 in conditioned media were assayed by zymography. MMP-2 and MMP-9 were increased in cortical astrocytes and co-cultures, whereas only MMP-2 was increased in neurons. Western blots showed that phosphorylated extracellular signal regulated kinase (ERK1/2) and p38 were rapidly upregulated in co-cultures after mechanical injury. No change in phosphorylated c-jun N-terminal kinase (JNK) was observed. In-gel kinase assays confirmed this lack of response in the JNK pathway. Treatment with either 10 microM of U0126 (a MAP kinase/ERK1/2 kinase inhibitor) or 10 microM of SB203580 (a p38 inhibitor) had no detectable effect on MMP-2 and MMP-9 levels after mechanical injury. However, combination treatment with both inhibitors significantly reduced secretion of MMP-9. Herein, we demonstrate that (1) resident brain cells secrete MMP after mechanical injury, (2) astrocytes are the main source of MMP-9 activity, and (3) ERK and p38 MAP kinases are upregulated after mechanical injury, and mediate the secretion of MMP-9.

Animals↗

PubMed2001

Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells.

Matrix metalloproteinases (MMPs) play a pivotal role in angiogenesis, atherogenesis, vascular remodeling after vascular injury, and instability of atherosclerotic plaque. The present study was undertaken to investigate the effect of lysophosphatidylcholine, a major component of oxidized low density lipoprotein (LDL), on the regulation of MMPs in cultured bovine aortic endothelial cells (BAECs). Furthermore, we explored the potential role of oxidative stress in the regulation of MMP. LPC increased the secretion of gelatinolytic activity, as well as, protein of MMP-2 from BAECs. The stimulation of BAEC with superoxide increased the production of MMP-2 and it also induced its activation. Electron spin resonance (ESR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin trap agent demonstrated that lysophosphatidycholine (LPC) induced generation of reactive oxygen (ROS) species from BAECs. The inhibition of NADH/NADPH oxidase, one of the potential sources of superoxide in endothelial cells, attenuated the effect of LPC. Our findings suggest that LPC might activate the endothelial NADH/NADPH oxidase to enhance superoxide production, and it might, in turn, enhance MMP-2 induction.

Animals↗

PubMed2003

Secretion of matrix metalloproteinase-9 by the proinflammatory cytokine, IL-1beta: a role for the dual signalling pathways, Akt and Erk.

BACKGROUND: Matrix metalloproteinases including MMP-9 mediate matrix destruction during chronic inflammatory diseases such as arthritis and atherosclerosis. MMP-9 up-regulation by inflammatory cytokines involve interactions between several transcription factors including activator protein-1 and NFkappaB. The upstream regulatory pathways are less well understood. RESULTS: To search for the mechanism of tissue destruction in the process of inflammatory disorders, we investigated the signalling pathway critical for the activation of MMP-9 expression and secretion by IL-1beta. Treatment of Balb 3T3 cells with IL-1beta activated MMP-9 transcription and subsequent secretion in a time- and dose-dependent manner. Concomitantly, IL-1beta treatment of cells activated phosphorylation of Akt, Erk and p38. Treatment of cells with either LY294002, a PI3K inhibitor, or expression of a dominant negative form of Akt drastically suppressed the IL-1beta-dependent secretion of MMP-9. Pretreatment of cells with a MEK1 inhibitor, U0126, also strongly inhibited IL-1beta-dependent secretion of MMP-9. In contrast, pre-treatment with a specific p38 kinase inhibitor, SB203580, had no effect on IL-1beta-dependent secretion of MMP-9. In addition, cells expressing constitutively active form of Akt or MEK1 showed no clear activation of MMP-9 secretion, whereas these cells responded well to IL-1beta treatment. However, co-transfection of cells with both active Akt and MEK1 was sufficient to induce MMP-9 secretion without stimulation with IL-1beta. CONCLUSION: Taken together, our results suggest that IL-1beta stimulation of cells activates MMP-9 secretion by the activation of the dual signalling pathways, the PI3K-Akt and MEK1-Erk and constitutive activation of these pathways were sufficient to induce MMP-9 secretion.

Animals↗

PubMed2006

Ethanol stimulates the secretion of matrix metalloproteinases 2 and 9 in MCF-7 human breast cancer cells.

Alcohol consumption is a well-established risk factor for hormone-dependent breast cancer. In vitro studies performed to understand the mechanisms by which ethanol acts on breast cancer cells have shown that this compound stimulates both proliferation and migration. In the present study, we show by gelatin zymography that, when exposed to ethanol, MCF-7 human breast cancer cells display a higher amount of active metalloproteinases (MMP) 2 and 9 in their culture medium. This increase is somewhat higher than those observed in the case of 17beta-estradiol (E2) exposure. As expected, anti-estrogen ICI 182,780 inhibits the E2-induced overexpression of a well-known estrogen responsive gene, the progesterone receptor, in MCF-7 cells. ICI 182,780 also inhibits the E2-induced increase in MMP-2 and -9 secretion. Nevertheless, in the case of ethanol exposure, this ER ant-agonist was only efficient on MMP-9 secretion. In addition, although MMP-9 transcription was not sensitive to E2 or ethanol, MMP-2 transcription was stimulated in MCF-7 cells exposed to ethanol. Collectively, these results give new insights into the effects of alcohol on breast cancer cell migration, which are not due solely to an estrogen-like activity of alcohol.

Breast Neoplasms↗

PubMed2005

HAb18G/CD147 enhances the secretion of matrix metalloproteinases (MMP) via cGMP/NO-sensitive capacitative calcium entry (CCE) and accordingly attenuates adhesion ability of fibroblasts.

The present study examined the effect of hepatoma-associated antigen HAb18G (homologous to CD147) expression on the NO/cGMP-regulated Ca2+ mobilization to induce matrix metalloproteinases (MMP) production and attenuate adhesion ability of mouse fibroblast NIH/3T3 cells. HAb18G/CD147 cDNA was transfected into fibroblast 3T3 cells to obtain a cell line stably expressing HAb18G/CD147, t3T3, as demonstrated by immunofluorescence staining and flow cytometry assays. 8-Bromo-cGMP inhibited the thapsigargin-induced Ca2+ entry in 3T3 cells, whereas an inhibitor of protein kinase G, KT5823 (1 microM), led to an increase in Ca2+ entry. Expression of HAb18G/CD147 in t3T3 cells decreased the inhibitory response to cGMP. A similar effect on the Ca2+ entry was observed in 3T3 cells in response to an NO donor, (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). The inhibitory effect of SNAP on the thapsigargin-induced Ca2+ entry was also reduced in HAb18G/CD147-expressing t3T3 cells, indicating a role for HAb18G/CD 147 in NO/cGMP-regulated Ca2+ entry. Results of gelatin zymography assays showed that addition of extracellular Ca2+ induced MMP (MMP-2, MMP-9) release and activation in a dose-dependent manner, and expression of HAb18G/CD147 enhanced the secretion of MMP-2 and MMP-9 in 3T3 cells. 8-Bromo-cGMP and SNAP reduced the production of MMP in 3T3 cells but not in t3T3 with HAb18G/CD147 expression. RT-PCR experiments substantiated that the expression of MMP-2 and MMP-9 mRNA in HAb18G/CD 147-expressing t3T3 cell was significantly greater than that in 3T3 cells. Experiments investigating adhesion potentials demonstrated that HAb18G/CD147-expressing t3T3 cells pretreated with Ca2+ attached to Matrigel-coated culture plates significantly less efficiently than 3T3 cells. The proportion of attached cells could be increased by treatment with 8-bromo-cGMP and SNAP in 3T3 cells, but not in t3T3. These results suggest that HAb18G/CD147 attenuates adhesion potentials in fibroblasts by enhancing the secretion of MMP through NO/cGMP-sensitive capacitative Ca2+ entry.

3T3 Cells↗

PubMed2005

Corticotropin-releasing hormone and urocortin induce secretion of matrix metalloproteinase-9 (MMP-9) without change in tissue inhibitors of MMP-1 by cultured cells from human placenta and fetal membranes.

CONTEXT: Matrix metalloproteinases (MMPs) are essential for human parturition due to their degrading of the extracellular matrix. CRH and urocortin (Ucn) are thought to play a central role in the mechanisms controlling human pregnancy and parturition. OBJECTIVE, DESIGN, AND SETTING: The aim of this study was to assess the effects of CRH and Ucn on MMP-9 and tissue inhibitors of MMP-1 (TIMP-1) protein and/or mRNA levels in vitro. Zymography, Western blotting, real-time RT-PCR, and culture/treatments of purified sycytiotrophoblast, chorion trophoblast, and amniotic epithelial cells from human placenta and fetal membranes were performed. RESULTS: CRH and Ucn significantly increased MMP-9 protein secretion from cultured chorionic trophoblast, amnion epithelial, and syncytiotrophoblast cells (P < 0.01, compared with control, respectively), but there was no effect on TIMP-1 secretion and MMP-9 mRNA expression. Antalarmin (a CRH receptor type 1 antagonist) significantly blocked CRH- and Ucn-induced pro-MMP-9 secretion from three cell types (P < 0.01, compared with treatment with CRH and Ucn alone, respectively). Antisauvagine 30 (a CRH receptor type 2 antagonist) resulted in a significant reduction in CRH- and Ucn-induced secretion from chorionic trophoblast cells (P < 0.05) and syncytiotrophoblast cells (P < 0.01) compared with treatment with CRH and Ucn alone, respectively, but had no significant effect on amniotic epithelial cells. CONCLUSION: Our results suggest that CRH and Ucn may play a role in the mechanisms controlling human parturition and preterm delivery not only by affecting myometrial contractility, but also by increasing local MMP activity in placenta and fetal membranes, thereby contributing to membrane rupture with the onset and progression of human labor.

Amnion↗

PubMed1994

Regulation of 92-kD gelatinase release in HL-60 leukemia cells: tumor necrosis factor-alpha as an autocrine stimulus for basal- and phorbol ester-induced secretion.

Matrix metalloproteinase 9 (MMP-9), also known as 92-kD type IV collagenase/gelatinase, is believed to play a critical role in tumor invasion and metastasis. Here, we report that MMP-9 was constitutively released from the human promyelocytic cell line HL-60 as determined by zymographic analysis. Tumor necrosis factor-alpha (TNF-alpha) enhanced the enzyme release threefold to fourfold and the protein kinase C (PKC) activator and differentiation inducer 12-O-tetradecanoylphorbol-13-acetate (TPA) eightfold to ninefold. Gelatinase induction by TNF-alpha and TPA was inhibited by actinomycin D or cycloheximide, indicating that de novo protein synthesis was required. Neutralizing monoclonal antibodies to TNF-alpha (anti-TNF-alpha) decreased the basal MMP-9 release of these cells. In addition, these antibodies also significantly interfered with the TPA-induced enzyme release. Agents that inhibit TNF-alpha expression in HL-60 cells, such as pentoxifylline and dexamethasone, completely abrogated both the constitutive and TPA-evoked MMP-9 release. Diethyldithiocarbamate, which is known to stimulate TNF-alpha production in HL-60 cells, exerted a positive effect on MMP-9 release in untreated cells but was inhibitory in TPA-treated HL-60 cells. The PKC inhibitor staurosporine at low concentrations (100 ng/mL) caused a significant augmentation of MMP-9 release in untreated cultures that was blocked by the addition of anti-TNF-alpha. High concentrations (2 mumol/L) of staurosporine completely abolished the extracellular enzyme activity both in untreated and TPA-stimulated cells. These results suggest, that TNF-alpha is required for basal and PKC-mediated MMP-9 release in HL-60 leukemia cells. Thus, MMP-9 secretion may be regulated by TNF-alpha not only in a paracrine but also in an autocrine fashion. This may potentiate the matrix degradative capacity of immature leukemic cells in the processes of bone marrow egress and the evasion of these cells into peripheral tissue.

Alkaloids↗

PubMed2002

Association of serum MMP-9 with autoantibodies against oxidized LDL.

Monocyte-derived macrophages in atherosclerotic plaques secrete matrix metalloproteinases (MMPs), which may contribute to plaque rupture. There has been much speculation as to which factors precipitate in the arterial inflammation. Oxidized low density lipoprotein (oxLDL) has been suggested to have proinflammatory properties, and it has been shown to increase matrix metalloproteinase-9 (MMP-9) secretion by macrophages in vitro. We determined serum MMP-9 concentration and autoantibodies against oxLDL by ELISA in men with angina pectoris (n=243) and age-matched controls (n=238). The association between serum MMP-9 concentration and autoantibodies against oxLDL was evaluated. Autoantibody level against oxLDL, expressed in optical density units, was significantly higher in subjects with angina pectoris compared to controls (0.100+/-0.064 versus 0.088+/-0.051, respectively, P=0.030), but serum levels of MMP-9 did not differ significantly between these groups (54.2+/-29.9 versus 50.6+/-23.1 microg/l). However, autoantibodies against oxLDL correlated positively with serum MMP-9 (r=0.21, P<0.001). In a multiple regression model (including age, diastolic blood pressure, cholesterol, HDL cholesterol, triglycerides, BMI, smoking and MMP-9) serum MMP-9 (beta=0.200, P<0.001) and smoking (beta=0.179, P<0.001) were significantly associated with autoantibodies against oxLDL. In conclusion, autoantibodies against oxLDL were positively associated with angina pectoris and serum MMP-9. Since autoantibody level against oxLDL could be expected to reflect the degree of oxLDL in the vessel wall, our results suggest that oxLDL is associated with MMP-9 in vivo.

Aged↗