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Results for “Matrix Metalloproteinases, Secreted”

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PubMed2005

Characterization of Toll-like receptors in primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C) on the regulation of Toll-like receptors, adaptor proteins and inflammatory response.

BACKGROUND: Bacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma. Since the lung epithelium is a major source of various inflammatory mediators that affect the immune response, we analyzed the inflammatory reaction of primary lung epithelial cells to different microbial molecules that are recognized by Toll-like receptors (TLR). METHODS: The effects of TLR ligands on primary small airway epithelial cells were analyzed in detail with respect to cytokine, chemokine and matrix metalloproteinase secretion. In addition, the regulation of the expression of TLRs and their adaptor proteins in small airway epithelial cells was investigated. RESULTS: Our data demonstrate that poly(I:C), a synthetic analog of viral dsRNA, mediated the strongest proinflammatory effects among the tested ligands, including an increased secretion of IL-6, IL-8, TNF-alpha, GM-CSF, GRO-alpha, TARC, MCP-1, MIP-3alpha, RANTES, IFN-beta, IP-10 and ITAC as well as an increased release of MMP-1, MMP-8, MMP-9, MMP-10 and MMP-13. Furthermore, our data show that poly(I:C) as well as type-1 and type-2 cytokines have a pronounced effect on the expression of TLRs and molecules involved in TLR signaling in small airway epithelial cells. Poly(I:C) induced an elevated expression of TLR1, TLR2 and TLR3 and increased the gene expression of the general TLR adaptor MyD88 and IRAK-2. Simultaneously, poly(I:C) decreased the expression of TLR5, TLR6 and TOLLIP. CONCLUSION: Poly(I:C), an analog of viral dsRNA and a TLR3 ligand, triggers a strong inflammatory response in small airway epithelial cells that is likely to contribute to viral exacerbations of pulmonary diseases like asthma or COPD. The pronounced effects of poly(I:C) on the expression of Toll-like receptors and molecules involved in TLR signaling is assumed to influence the immune response of the lung epithelium to viral and bacterial infections. Likewise, the regulation of TLR expression by type-1 and type-2 cytokines is important considering the impact of exogenous and endogenous TLR ligands on Th1 or Th2 driven pulmonary inflammations like COPD or asthma, respectively.

Journal Article↗

PubMed1999

Examining the relationship between the gelatinolytic balance and the invasive capacity of endothelial cells.

Angiogenesis and the formation of new blood vessels requires coordinated regulation of matrix proteolysis and endothelial cell migration. Cellular proteolytic capacity is the balance between secreted matrix metalloproteinases (MMP) and their inhibitors (TIMPs). We have examined the regulation of the gelatinase/TIMP balance by transforming growth factor-beta1 (TGF-beta1) and phorbol myristate acetate (PMA) in bovine endothelial cells. The low constitutive expression of gelatinase A/MMP-2 was upregulated by TGF-beta1 in a dose-dependent manner. Gelatinase B/MMP-9 was only detected upon treatment with either PMA or TGF-beta1. However, addition of both factors together revealed a striking synergistic effect causing upregulation of MMP-9 and downregulation of TIMPs, thereby increasing the net MMP-9/TIMP balance and the gelatinolytic capacity. These effects were observed at both the protein and mRNA levels. We demonstrate that changes in different members of the Jun oncogene family with distinct transactivation properties may account for this synergistic effect. We investigated the contribution of these changes in gelatinolytic balance to endothelial cell migration and invasion. The endothelial cells showed increased cell motility in response to PMA, but the addition of TGF-beta1 had an inhibitory effect. Hence, regulation of the MMP-9/TIMP balance failed to correlate with the migratory or invasive capacity. These results question a direct role for MMP-9 in endothelial cell motility and suggest that gelatinases may contribute in alternative ways to the angiogenic process.

Animals↗

PubMed1997

Inhibition of collagenases from mouse lung carcinoma cells by green tea catechins and black tea theaflavins.

Theaflavin and theaflavin digallate, which are components of black tea were examined by in vitro invasion assay with mouse Lewis lung carcinoma LL2-Lu3 cells, which are highly metastatic. The compounds inhibited invasion by the tumor cells. Gelatin zymography showed that the cells secreted matrix metalloproteinases (MMPs), probably including MMP-2 and MMP-9, which may be involved in tumor cell invasion and metastasis. Theaflavin and theaflavin digallate also inhibited MMPs from the culture medium of these tumor cells, as did (-)-epigallocatechin gallate. These results suggest that theaflavin, theaflavin digallate, and (-)-epigallocatechin gallate inhibit tumor cell invasion by inhibiting type IV collagenases of the LL2-Lu3 cells.

Animals↗

PubMed2004

Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 3: brain tumor invasiveness.

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Cellular invasion of surrounding brain is one of the key features of brain tumor behavior and is currently under evaluation for potential therapeutic targets. Tumor invasion occurs in the context of the extracellular matrix (ECM) of the brain and involves the interaction between cell-surface adhesion molecules, such as integrins and proteins embedded within the ECM. The overexpression of integrins is often associated with invasive behavior and can be inhibited by targeted approaches such as antibodies, antisense constructs and cyclic peptides. Tumor cell-secreted matrix metalloproteinases and serine proteinases degrade ECM proteins and provide space for movement and infiltration. The expression of proteinases positively correlates with tumor grade and infiltrative capacity. Proteinase activity can be reduced by several methods, including antibodies and small-molecule inhibitors such as marimastat. Early clinical trials suggest that marimastat may have activity in combination with traditional chemotherapy regimens. Further development of targeted therapies designed to inhibit tumor infiltration, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with brain tumors.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Gelatinase-B (matrix metalloproteinase-9; MMP-9) secretion is involved in the migratory phase of human and murine muscle cell cultures.

The remodelling of connective tissue components is a fundamental requirement for a number of pivotal processes in cell biology. These may include myoblast migration and fusion during development and regeneration. In other systems, similar biological processes are facilitated by secretion of the matrix metalloproteinases (MMPs), especially the gelatinases. This study investigated the activity of the gelatinases MMP-2 and 9 by zymography on cell conditioned media in cultures of cells derived from explants of the human masseter muscle and in the murine myoblast cell-line C2C12. Expression of MMP-9 by western blotting and TIMP-1, the major inhibitor of MMPs, by northern blotting, during all phases of myoblast proliferation, migration, alignment and fusion, was also measured. Irrespective of the origin of the cultures, MMP-9 activity was secreted only by single cell and pre-fusion cultures whilst MMP-2 activity was secreted at all stages as well as by myotubes. The loss of MMP-9 activity was due to the loss of MMP-9 protein expression. TIMP-1 mRNA was not detectable at the single cell stage but its expression increased as cells progressed through the pre-fusion and post-fusion stages to reach a maximal in myotube containing cultures. Migration of cells derived from human masseter muscle was inhibited, using a specific anti-MMP-9 blocking monoclonal antibody (6-6B). These data are consistent with the concept that regulation of matrix turnover via MMP-9 may be involved in the events leading to myotube formation, including migration. Loss of expression of this enzyme and expression of TIMP-1 mRNA is associated with myotube containing cultures. Consequently, the ratio between MMPs and TIMPs maybe important in determining myoblast migration and differentiation.

Animals↗

PubMed2002

Effect of hydrosalpinx fluid on secretion of trophoblastic matrix metalloproteinases.

OBJECTIVE: To determine if hydrosalpinx fluid affects trophoblastic metalloproteinases (MMPs) secretion. DESIGN: Measurement of the effect of hydrosalpinx and peritoneal fluids (as controls) added to the medium on the MMPs secreted by cytotrophoblastic cells. SETTING: Academic research center. PATIENT(S): Five samples of hydrosalpinx fluid were obtained at the time of ovocyte retrieval. Three samples of peritoneal fluids were collected at laparoscopic sterilization. MAIN OUTCOME MEASURE(S): The concentration and activity of MMP-2 and MMP-9, the concentration of the tissue inhibitor of metalloproteinases (TIMP-1), and the total gelatinolytic activity of the cytotrophoblastic cells were measured in the culture medium. RESULT(S): Hydrosalpinx significantly stimulated MMP-2, MMP-9, and TIMP-1. The net result was a significant stimulation of the total gelatinolytic activity. Peritoneal fluids increased MMP-2, MMP-9, and TIMP-1 concentrations, but the total gelatinolytic activity was not modified. CONCLUSION(S): In contrast to peritoneal fluids, hydrosalpinx stimulates the total gelatinolytic activity of cytotrophoblastic cells. This might indicate that the effect of hydrosalpinx on implantation rates may not be due to an inhibition of the capacity of an embryo to invade the endometrium. However, the stimulatory effect of hydrosalpinx on the net gelatinolytic activity could partly explain the increased incidence of ectopic pregnancies that have been described in the presence of hydrosalpinx.

Adult↗

PubMed2000

Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation.

Matrix metalloproteinases characterized so far are either secreted or membrane anchored via a type I transmembrane domain or a glycosylphosphatidylinositol linkage. Lacking either membrane-anchoring mechanism, the newly discovered CA-MMP/MMP-23 was reported to be expressed as a cell-associated protein. In this report, we present evidence that CA-MMP is expressed as an integral membrane zymogen with an N-terminal signal anchor, and secreted as a fully processed mature enzyme. We further demonstrate that L(20)GAALSGLCLLSALALL(36) is required for this unique membrane localization as a signal anchor and its secretion is regulated by a proprotein convertase motif RRRR(79) sandwiched between its pro- and catalytic domains. Thus, CA-MMP is a type II transmembrane MMP that can be regulated by a single proteolytic cleavage for both activation and secretion, establishing a novel paradigm for protein trafficking and processing within the secretory pathway.

Amino Acid Motifs↗

PubMed2006

Ultraviolet B-induced matrix metalloproteinase-1 and -3 secretions are mediated via PTEN/Akt pathway in human dermal fibroblasts.

Matrix Metalloproteinases (MMPs) are crucial enzymes for ultraviolet irradiation-induced photoaging in human skin. Ultraviolet B (UVB) stimulates dermal fibroblasts to increase MMP-1 and -3 expression and extracellular matrix (ECM) degradation in photoaging. We investigated whether phosphatase and tensin homolog (PTEN)/Akt pathway is involved in secretions of MMP-1 and -3 in human dermal fibroblasts. The increase in MMP-1 and -3 expression and secretion occurred along with the increase in PTEN and Akt phosphorylation by UVB irradiation in a dose- and time-dependent manner. However, treatment with a casein kinase 2 inhibitor, 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, inhibited their phosphorylations and MMP-1 and -3 secretions. Transfection of wild-type PTEN (Wt-PTEN) decreased basal and UVB-induced MMP-1 and -3 secretions, as well as activator protein-1 (AP-1) activity, while transfection of small interference RNA of PTEN (siRNA-PTEN), phosphatase-inactive PTEN (C124S-PTEN), or lipid phosphatase-inactive PTEN (G129E-PTEN) increased basal or UVB-induced MMP-1 and -3 secretions and AP-1 activity. Transfection of constitutively active Akt (Myr-Akt) also increased basal or UVB-induced MMP-1 and -3 secretions, as well as AP-1 activity. However, transfection of kinase-inactive Akt (K179M-Akt) decreased their secretions, but showed no significant change of AP-1 activity without UVB irradiation, and a significant increase of AP-1 activity with UVB irradiation. Treatment with the phosphatidylinositol 3-kinase inhibitors, LY294002 or wortmannin, downregulated basal and UVB-induced MMP-1 and -3 secretions. In conclusion, UVB irradiation increases PTEN and Akt phosphorylation in human dermal fibroblasts, and these inhibition of PTEN and activation of Akt by phosphorylation are involved in UVB-induced MMP-1 and -3 secretions partly through upregulation of AP-1 activity.

Cells, Cultured↗

PubMed1995

Differences in expression of metalloproteinases and plasminogen activators in murine melanocytes and B16 melanoma variants: lack of association with in vitro invasion.

We investigated in vitro chemotactic responses to fibronectin and laminin, invasion through reconstituted basement membrane (Matrigel) and secretion of matrix metalloproteinases and plasminogen activators by non-tumorigenic Mel-ab melanocytes; B16 melanoma; and the metastatic sublines, B16F1, B16F10 and B16BL6. In vitro chemotactic and invasive ability were not associated with in vivo metastatic potential. Secretion of various matrix-degrading enzymes was not related to in vitro invasion. Conditioned media from all B16 melanoma sublines, but not from Mel-ab cells, contained the M(r) 92,000 progelatinase. The activated M(r) 85,000 species was present only in conditioned media from Mel-ab, B16 and B16F1 cells. Mel-ab cells secreted copious amounts of the M(r) 72,000 progelatinase, and the M(r) 66,000 active form was also present in conditioned media. Secretion of the M(r) 72,000 progelatinase by B16 melanoma sublines was markedly lower, and only conditioned media from B16 cells contained the activated M(r) 66,000 form. Furthermore, cell lysates of Mel-ab cells contained a M(r) 67,000 metalloproteinase which was absent in the tumor cells. All cells secreted tissue plasminogen activator; however, the metastatic B16F1, B16F10 and B16-BL6 cells also secreted urokinase plasminogen activator. Our results indicate that matrix metalloproteinase secretion by itself is not associated with tumorigenicity or metastatic potential. Secretion of urokinase plasminogen activator, and not tissue plasminogen activator, reflected the metastatic characteristics of the B16 melanoma tumor sublines.

Animals↗

PubMed2006

Effect of Ukrain on matrix metalloproteinase-2 and Secreted Protein Acidic and Rich in Cysteine (SPARC) expression in human glioblastoma cells.

Glioblastoma is a highly malignant brain tumor with a highly invasive phenotype and hence an unfavorable prognosis even in response to multidisciplinary treatment strategies. Ukrain, a semi-synthetic thiophosphoric acid derivative of the purified alkaloid chelidonine, has been used in the therapy of several solid tumors, but little is known about its effect on glioblastoma and, in general, about the molecular mechanisms responsible for its effects. We used RT-PCR, Western blot and SDS-zymography to investigate the effects of three doses of Ukrain (0.1, 1 and 10 micromol/l) on the expression of genes and proteins involved in the extracellular matrix remodeling associated with tumor invasion in human cultured glioblastoma cells treated for 24, 48 and 72 h. We analyzed the expression of matrix metalloproteinase-2 and -9, the main mediators of glioblastoma invasiveness, and secreted protein acidic and rich in cysteine (SPARC), involved in the regulation of cell-matrix interactions. There was a significant, dose-related decrease of glioblastoma cell proliferation and a tendency to downregulation of SPARC at the protein level 72 h after 10 micromol/l Ukrain, suggesting the drug may be a useful therapeutic tool for brain tumors.

Antineoplastic Agents↗

PubMed2006

Comparative effects of interferon-gamma and all- trans retinoic acid on secreted and surface-associated matrix metalloproteinase-9 expression of human monocytes.

Matrix metalloproteinase-9 is involved in inflammation and tumor progression. We previously demonstrated that interferon type I (alpha/beta) and II (gamma) inhibit matrix metalloproteinase-9 (92kDa) gene expression on lymphocytes from patients with B chronic lymphocytic leukemia and human monocytes. Since all-trans retinoic acid (ATRA) can regulate some interferon -responsive genes, we studied here the effects of all-trans retinoic acid onto matrix metalloproteinase-9 levels in these cells. By using RT-PCR, ELISA and zymography experiments, we showed that all-trans retinoic acid down-regulated matrix metalloproteinase-9 synthesis (mRNA,protein) and secretion. The inhibitory action of all-trans retinoic acid toward matrix metalloproteinase-9 was however not associated with the STAT1/IRF-1 pathway involved in interferon-mediated matrix metalloproteinase-9 inhibition indicating that all-trans retinoic acid did not bypass IFN receptor signaling. Using flow cytometry, we detected on the surface of monocytes low expression of matrix metalloproteinase-9 and Fc-gammaRI, and high expression of HLA-DR, beta1 and beta2 integrins. Enhancement of Fc-gammaRI and HLA-DR on monocytes by interferon-gamma, but not by all-trans retinoic acid, was accompanied by up-regulation of surface matrix metalloproteinase-9. Furthermore, we showed that all-trans retinoic acid down-regulated matrix metalloproteinase-9 expression in lymphocytes of untreated patients with early stage B chronic lymphocytic leukemia. Together, our data suggest the potential relevance of all-trans retinoic acid as a pharmacological tool to attenuate matrix metalloproteinase-9 secretion in pathological situations.

Antigens, Surface↗

PubMed1997

Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma.

BACKGROUND & AIMS: Matrix metalloproteinases have been implicated in invasion and metastasis of various human malignant tumors, but its role in human hepatocellular carcinoma has not been characterized in detail. The aim of the present study was to examine the secretion and activation of metalloproteinases in liver tissues from patients with hepatocellular carcinoma and evaluate its relationship with clinicopathologic characteristics. METHODS: Activity of metalloproteinases was measured in 30 surgical specimen pairs of human primary hepatocellular carcinoma and adjacent nontumoral liver and in five cultured human hepatoma cell lines using zymography. A comparison of this activity with clinicopathological features was made. RESULTS: In the liver tissues, enhanced secretion of active forms of gelatinase A and matrilysin was associated with portal venous invasion (P < 0.05, respectively), intrahepatic metastasis (P < 0.05, respectively), and recurrence within the first postoperative year (P < 0.01 and P < 0.05, respectively). Enhanced messenger RNA expression for membrane type 1-matrix metalloproteinase was observed in 22 of 30 cases and associated with capsule invasion and the activation of progelatinase A (P < 0.05, respectively). CONCLUSIONS: Active gelatinase A, active matrilysin, and membrane type 1-matrix metalloproteinase may play an important role in tumor spread of human hepatocellular carcinoma.

Carcinoma, Hepatocellular↗

PubMed2002

Monocyte-derived dendritic cells express and secrete matrix-degrading metalloproteinases and their inhibitors and are imbalanced in multiple sclerosis.

Dendritic cells (DC) are antigen-presenting cells (APC) that most efficiently initiate and control immune responses. Migration processes of blood DC are crucial to exert their professional antigen-presenting functions. Matrix-degrading metalloproteinases (MMP) are proteolytic enzymes, which are considered to be key enzymes in extracellular matrix (ECM) turnover and mediators of cell migration. Tissue inhibitors of metalloproteinases (TIMP) are important regulators of MMP activity. Here we investigate whether blood monocyte-derived immature DC (iDC) and mature DC (mDC) express, produce and secrete functionally active MMP-1, -2, -3 and -9 and their inhibitors TIMP-1 and -2, and examine their involvement in multiple sclerosis (MS). On mRNA level, we observed high numbers of MMP-2 and TIMP-2 mRNA expressing iDC in MS. On protein level, high percentages of MMP-1, -2 and -9 expressing iDC by flow cytometry, and high MMP-1 secretion by Western blot together with high MMP-2 and -9 activities in iDC supernatants as studied with zymography were observed. Similarly, MS is associated with high percentages of MMP-2 and -3 and of TIMP-1 expressing mDC by flow cytometry together with high MMP-3 secretion and high MMP-9 activity in culture supernatants. Spontaneous migratory capacity of both iDC and mDC over ECM-coated filters was higher in MS compared to healthy controls (HC). In conclusion, blood monocyte-derived iDC and mDC express, produce and secrete several MMP and TIMP. Alterations in these molecules as observed in MS may be functionally important for DC functioning.

Adult↗

PubMed2005

Effect of sodium butyrate on pro-matrix metalloproteinase-9 and -2 differential secretion in pediatric tumors and cell lines.

Matrix metalloproteinases (MMPs) are enzymes responsible for extracellular matrix degradation and contribute to local and distant cell invasion during cancer progression or metastasis. The effects of chromatin structure on gene expression and the use of histone deacetylase inhibitors such as sodium butyrate (NaBu) may directly influence pro-MMPs secretion. In the present study, we evaluated the effect of NaBu on pro-MMP-9 and pro-MMP-2 secretion in human Jurkat and HT1080 cells, and in 36 pediatric solid tumors. Cell lines and samples were exposed to 8 mM of NaBu and proteinase activity was evaluated in the supernatant by gelatin zymograms. Our results showed, for Jurkat cells treated with NaBu, increases of 2-fold and 1.5-fold in pro-MMP-9 and pro-MMP-2 secretion, respectively. A 50% decrease in pro-MMP-9 secretion due to NaBu was observed in HT1080 cells. NaBu induced a 0.62 reduction in levels of pro-MMP-9 secretion in untreated tumors. For cell lines and some NaBu-treated tumors we found histone H4 hyperacetylation. We conclude that pro-MMPs gene expression and their secretion can be epigenetically mis-regulated in tumoral processes.

Acetylation↗

PubMed2005

Effect of melatonin on secreted and induced matrix metalloproteinase-9 and -2 activity during prevention of indomethacin-induced gastric ulcer.

Matrix metalloproteinases (MMPs) maintain the crucial role in physiological turnover of extracellular matrix (ECM) proteins in gastric tissues. However, a little is known about the relationship of MMPs with ECM degradation during gastric ulceration and ECM remodeling during healing. Our objective was to investigate the effect of melatonin (N-acetyl-5 methoxytryptamine) on the regulation of MMP-9 and MMP-2 activity during prevention of gastric ulcer. In the present study, biochemical and zymographic methods were used to analyze the mechanism of melatonin in indomethacin-induced gastric ulcer in a rat model. Our studies reveal that melatonin dose-dependently downregulates the expression and secretion of pro-MMP-9 which is induced (approximately 10-fold) during indomethacin-induced gastric ulceration. Furthermore, melatonin prevents gastric ulceration in a dose-dependent manner through upregulation (approximately two- to threefold) of both pro-MMP-2 and active MMP-2 at the level of induction as well as secretion. It also prevents gastric ulcers by blocking glutathione depletion and lipid peroxidation in cytosolic and microsomal fractions. The novel findings of this study are attributed to the attenuation of the pro-MMP-9 and increase of MMP-2 activity by pretreatment with melatonin. The finding defines one of the MMP-mediated pathways for melatonin's action in gastric ulcer.

Animals↗

PubMed1995

Human vascular smooth muscle cell-monocyte interactions and metalloproteinase secretion in culture.

Degradation of the atherosclerotic plaque extracellular matrix could destabilize the lesion, rendering it more prone to rupture. Both macrophages and vascular smooth muscle cells (SMCs) are potential sources of matrix metalloproteinases (MMPs), secreted enzymes that can digest vascular matrix. We explored interactions between human vascular SMCs and human monocytes that result in the secretion of interstitial collagenase (MMP-1) and stromelysin (MMP-3). Monocytes alone or those treated with SMC-conditioned media did not secrete these metalloproteinases as detectable by Western blot analysis. SMCs increased secretion of both MMP-1 and MMP-3 greater than 20-fold when cocultured with monocytes or when treated with monocyte-conditioned media. Addition of macrophage colony stimulating factor (< or = 1000 U/mL) to cocultures of monocytes and SMCs did not affect metalloproteinase secretion. Recombinant interleukin (IL)-1 receptor antagonist inhibited MMP-1 and MMP-3 induction in SMC cultures treated with monocyte-conditioned media (94% and 96% reduction, respectively), while a neutralizing antibody to tumor necrosis factor-alpha had no significant effect on metalloproteinase secretion. In contrast to the induction by monocyte-conditioned media of MMP-1 and MMP-3 secretion by SMCs, monocyte-conditioned media did not increase secretion of 72-kD gelatinase (MMP-2). Thus, monocytes induce MMP-1 and MMP-3 secretion by vascular SMCs through an IL-1-dependent mechanism. This response of SMCs to a defined macrophage product may contribute to plaque destabilization by mononuclear phagocytes in the lesion.

Cells, Cultured↗

PubMed1994

Modulation of production of matrix metalloproteinases from ovine endometrial cells by ovine trophoblast interferon.

Ovine trophoblast interferon modulates the secretion of a number of proteins by ovine endometrium, but only one of these proteins has so far been identified. We examined the effects of trophoblast interferon on the secretion of matrix metalloproteinase-1, -2 and -3 by cultured ovine endometrial cells and determined whether they are mediated via effects on prostaglandin synthesis. Both ovine trophoblast interferon (30 ng ml-1) and human recombinant interferon alpha (50 U ml-1) inhibited the production of latent matrix metalloproteinase-1 and -3 (P < 0.05), as measured by enzyme assays, but had no effect on the secretion of latent matrix metalloproteinase-2. These inhibitory effects were not overcome by PGE2 or PGF2 alpha (each 10 mumol l-1) either alone or in combination. Indomethacin (12 mumol l-1) similarly inhibited the production of latent matrix metalloproteinase-1 and -3, but production was partially restored by adding the prostaglandins either singly or in combination. PGE2 and PGF2 alpha together had no effect on enzyme production. These data were confirmed by gelatin and casein zymography. Northern analysis showed a 4.5-fold increase in the abundance of specific mRNA for latent matrix metalloproteinase-1 following treatment of cells with phorbol myristate acetate, but a marked decrease following interferon treatment. Thus, ovine trophoblast interferon inhibits the production of the latent forms of matrix metalloproteinase-1 and -3 by ovine endometrial cells, and this is independent of its effect on prostaglandin production.

Animals↗

PubMed2000

Interleukin-1alpha-dependent regulation of matrix metalloproteinase-9(MMP-9) secretion and activation in the epithelial cells of odontogenic jaw cysts.

Interleukin-1alpha (IL-1alpha) and matrix metalloproteinase-9 (MMP-9) are thought to be involved in odontogenic cyst expansion. In this study, we investigated the effects of IL-1alpha on the secretion and activation of MMP-9 in odontogenic jaw cysts. An active form of MMP-9 was present in odontogenic keratocyst (6 of 8 cases) fluids more frequently than dentigerous cyst (3 of 10 cases) and radicular cyst (3 of 10 cases) fluids, although proMMP-9 was present in all cyst fluids. Odontogenic keratocyst fragments in explant culture secreted a larger amount of IL-1alpha than dentigerous cyst and radicular cyst fragments in explant culture, and spontaneously secreted both proMMP-9 and an active form of MMP-9. The fragments of dentigerous cysts and radicular cysts secreted a small amount of proMMP-9, but no active form of MMP-9. Exogenously added recombinant human IL-1alpha (rhlL-1alpha) increased the secretion and activation of proMMP-9 in the fragments of dentigerous cysts and radicular cysts. The epithelial cells isolated from odontogenic keratocysts secreted IL-1alpha and proMMP-9 without stimulation. Under the cultivation on a fibronectin-coated dish, rhIL-1alpha increased the secretion of proMMP-9 from the epithelial cells in a dose-dependent manner. Moreover, rhIL-1alpha induced the secretion of proMMP-3 and plasminogen activator urokinase (u-PA) from the epithelial cells, and converted the secreted proMMP-3 to the active form in the presence of plasminogen. The secreted proMMP-9 was also activated in the presence of rhIL-1alpha and plasminogen. Hence, our results suggest that IL-1alpha may up-regulate not only proMMP-9 secretion but also proMMP-9 activation by inducing proMMP-3 and u-PA production in the cyst epithelial cells by autocrine/paracrine regulatory mechanisms.

Autocrine Communication↗