Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During early human pregnancy, fetal cytotrophoblasts rapidly invade the uterus. This process has many similarities to tumor invasion, except that the extent and the timing of cytotrophoblast invasion are carefully regulated. Therefore, this system is particularly useful for studying mechanisms that regulate invasive processes. Previously, we showed that production and activation of the 92-kDa type IV collagenase (matrix metalloproteinase(MMP)-9) is necessary for cytotrophoblast invasion in vitro. In other systems, interleukin (IL)-1 beta is an important regulator of matrix-degrading metalloproteinases. Therefore, we investigated trophoblast production of IL-1 beta and its receptors, as well as the effects of this cytokine on cytotrophoblast metalloproteinase activity and invasion. The results showed that release of IL-1 beta parallels the invasive potential of the cytotrophoblasts; the highest levels are produced by first trimester cells and the lowest levels by term cells. Immunoprecipitation showed that cytotrophoblasts express the 80-kDa type I IL-1 receptor, suggesting that autocrine effects are possible. IL-1 beta stimulated trophoblast MMP-9 secretion (by a mechanism that required nascent mRNA and protein synthesis) as well as metalloproteinase activity and invasion of Matrigel. Increasing (by lipopolysaccharide treatment) or decreasing (by glucocorticoid treatment) IL-1 beta production had parallel effects on MMP-9 secretion, metalloproteinase activity, and invasion. Because IL-1 beta and corticosteroids are present in high concentrations at the maternal-fetal interface, normal trophoblast invasion may be regulated, in part, by their opposing actions. In contrast, stimulation of cytotrophoblast IL-1 beta secretion by lipopolysaccharide may play a role in the sequela of infected fetal membranes.
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PMID:Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. 800 17

Monocytes/macrophages are associated with chronic inflammatory lesions, such as periodontal disease and rheumatoid arthritis, in which there is extensive connective tissue destruction. Stimulation of human monocytes results in the production of matrix metalloproteinases (MMPs) via a prostaglandin E2 (PGE2)-cAMP-dependent pathway. Modulation of many monocyte functions by interleukin 10 (IL-10) suggested that this cytokine may influence the signal transduction pathway leading to the production of MMPs by monocytes. Pre-incubation of monocytes with IL-10 for 1 h prior to stimulation with ConA resulted in significant inhibition of prostaglandin H synthase-2 (PGHS-2, the inducible form of prostaglandin synthase). In contrast, PGHS-1, the constitutive PGHS, was not affected by IL-10. Suppression of PGHS-2 mRNA and protein levels was detected at 1 ng/ml of IL-10 with maximal inhibition at 20 ng/ml. Nuclear run-on transcription assays performed on monocytes exposed to ConA or the combination of ConA and IL-10 indicated that IL-10 treatment suppressed PGHS-2 expression at the level of transcription. Attenuation of PGHS-2 by IL-10 was accompanied by decreased prostaglandin production, including PGE2. The decrease in prostaglandin production was primarily related to the effect of IL-10 on PGHS-2, since the release of arachidonic acid was unaffected by this cytokine. The inhibition of PGE2 production by IL-10 resulted in the suppression of mRNA and protein for interstitial collagenase and 92-kDa type IV collagenase/gelatinase (gelatinase B). This conclusion is supported by the ability of exogenously added PGE2 or dibutyryl cAMP to restore the production of MMPs in IL-10-treated monocytes. Additionally, PGHS-2 was also restored by PGE2 or dibutyryl cAMP, indicating that PGHS-2 is regulated through a PGE2-cAMP amplification pathway. These data add further support to the anti-inflammatory properties of IL-10.
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PMID:Interleukin 10 suppression of monocyte prostaglandin H synthase-2. Mechanism of inhibition of prostaglandin-dependent matrix metalloproteinase production. 806 57

Gelatinase B is a regulated matrix metalloproteinase with an important role in the remodelling of extracellular matrices and of basement membranes. To study the structure and function of gelatinase B in the mouse, the cDNA was cloned from a macrophage cell line (WEHI-3). Using this cDNA, a cosmid clone with the mouse gene was isolated. The complete gene (8 kbp) was sequenced and compared with the human gene structure. There was 78% similarity at the cDNA level and the exon/intron structure of the murine gene was similar to the human counterpart. At the 5' untranslated side, 1200 bp of the promoter/enhancer region were sequenced and found to contain several transacting-factor-binding sites. The mRNA transcription-initiation site was determined by non-isotopic primer-extension analysis. Polymerase-chain-reaction amplification of cDNAs yielded indirect evidence for a reverse-transcription stop in WEHI-3 cell mRNA. The DNA-derived mouse-protein structure exhibited 82% similarity with the human one. This similarity was functionally reflected by cross-reactivity of the mouse protein with an antiserum against human gelatinase B. The production of murine gelatinase B was studied at the protein level by zymography and at the mRNA level by Northern blot analysis. In WEHI-3 cells the gelatinase B protein is induced by bacterial lipopolysaccharide, phorbol ester, double-stranded RNA and the cytokine interleukin-1. Regulation of activity and structural heterogeneity of gelatinase B in WEHI-3 cells were shown to occur at the gene regulatory level, by expression of the matrix metalloproteinase inhibitor TIMP-1, and by glycosylation of the secreted protein.
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PMID:Mouse gelatinase B. cDNA cloning, regulation of expression and glycosylation in WEHI-3 macrophages and gene organisation. 824 59

When human MG-63 osteosarcoma cells are triggered with IL-1 beta, they produce, among various other cytokines, also monocyte chemotactic proteins (MCPs). Homogeneous MCP-1, MCP-2 and MCP-3 were found to induce production of gelatinase B and chemotaxis of monocytes. Based on the almost complete amino acid sequence of natural MCP-3, two sets of degenerated oligonucleotides were used for the amplification of MCP-3 cDNA. Total RNA from stimulated MG-63 cells was reverse transcribed and PCRs done on the mRNA:cDNA duplex. Using the PCR-product, several cDNAs were isolated from a cDNA library of IL-1-stimulated MG-63 cells. From the cDNA sequence the complete primary structure of the protein was deduced: MCP-3 shows 71% and 58% amino acid homology with MCP-1 and MCP-2, respectively. Our study establishes MCP-3 as an inflammatory cytokine that regulates macrophage functions. Because MCP-3 is often produced by tumor cell lines and regulates protease secretion by macrophages, its production might also contribute to invasion and metastasis of cancer cells.
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PMID:Human monocyte chemotactic protein-3 (MCP-3): molecular cloning of the cDNA and comparison with other chemokines. 846 Oct 11

Extracellular matrix components as well as enzymes and enzyme-inhibitors controlling the turn-over of these components play an important role in the local control of testicular function. Zymographic analysis was used to study the secretion and the control of the secretion of gelatinase A (MMP-2) and B (MMP-9) by primary cultures of rat Sertoli cells and by subcultures of peritubular cells. Data on gelatinase A were complemented by measurement of the corresponding mRNA by Northern blot analysis. The agonists investigated included hormones (FSH, testosterone), second messengers (dbcAMP, phorbolester and a Ca(2+)- ionophore), interleukin-1 beta (IL-1 beta) and inducers of cytokine production (Concanavalin A: ConA; lipopolysaccharide: LPS; double stranded RNA: PIC). It is demonstrated that Sertoli cells originally secrete both gelatinase A and B. When maintained in serum-free medium, however, they rapidly lose the ability to secrete gelatinase B. After 3 days of culture gelatinase A remains the only measurable gelatinase in both Sertoli and peritubular cell cultures. The production in peritubular cells, however, exceeds that in Sertoli cells some 25-fold. This was confirmed by a 30-fold difference in the level of steady-state gelatinase A mRNA levels. Gelatinase A secretion and gelatinase A mRNA were stimulated by ovine FSH in Sertoli cells and by dbcAMP and ConA in both Sertoli and peritubular cells. IL-1 beta displayed measurable but limited stimulatory effects in both cell types. Interestingly, in peritubular cells but not in Sertoli cells, ConA stimulated the production of a lower MW species probably representing an activated form of gelatinase A. It is concluded that both the amounts of gelatinase A produced, the levels of the corresponding mRNA and the regulation differ in cultured peritubular cells and Sertoli cells. The lectin concanavalin A is a novel and potent inducer of gelatinase A. It resembles cytochalasin D in selectively inducing an activated form of gelatinase A in peritubular cells. The mechanism responsible for this selective effect warrants further investigation.
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PMID:Gelatinase A secretion and its control in peritubular and Sertoli cell cultures: effects of hormones, second messengers and inducers of cytokine production. 873 89

The 92 kDa matrix metalloproteinase (gelatinase B, MMP-9) plays a major role in the facilitation of tumor metastasis and in inflammatory disorders characterized by excessive matrix protein destruction. MMP-9 is transcriptionally induced in multiple cell types by exposure to the inflammatory mediators bacterial endotoxin, interleukin-1 (IL-1) or tumor necrosis factor-alpha (TNF-alpha). CT-2519, (1-(5-isothiocyanatohexyl)-3,7-dimethylxanthine), a synthetic small molecule from an anti-inflammatory compound library, was evaluated for its effect on endotoxin and cytokine-induced MMP-9 synthesis by a monocytic leukemic cell line, THP-1, and a monocyte/macrophage line, RAW 264.7. CT-2519 dose-dependently inhibited endotoxin and cytokine-induced synthesis of MMP-9 by these cells. Furthermore, both MMP-9 secretion and matrix invasion by cells of a human fibrosarcoma cell line, HT-1080, were inhibited by CT-2519 in a dose-dependent manner. Northern blot analyses and studies utilizing MMP-9 promoter constructs indicated that the inhibitory action of CT-2519 occurs at the level of transcriptional suppression. Given the observation that cellular activation by endotoxin, IL-1 and TNF-alpha may be mediated, at least in part, through induction of certain species of phosphatidic acid (PA), the effect of CT-2519 on lipid levels was analyzed. CT-2519 effectively reduced endotoxin-mediated increases in particular cellular lipid levels. Pharmacologic modulation of cytokine-dependent gene products, such as MMP-9, may offer an important therapeutic approach to the treatment of neoplastic and inflammatory disorders.
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PMID:Pharmacological inhibition of gelatinase B induction and tumor cell invasion. 875 12

Matrix metalloproteinases play an important role in tumor invasion, angiogenesis and inflammatory tissue destruction. The 72-kd gelatinase A is the most widely distributed. Along with the 92-kd gelatinase B, it plays an important role in basement membrane turnover. Gelatinase A is secreted as progelatinase A and, when activated, can cause extracellular matrix destruction. The physiologic mechanism of this activation is not well understood. Based on the importance of endothelial cells in inflammation and cancer, we sought in this study to systematically study the PMA-induced activation of endothelial cell progelatinase A. Using HUVEC, we demonstrated that PMA-induced activation of progelatinase A in these vascular endothelial cells (a) was protein kinase C-dependent as it was blocked by H-7; (b) occurred through cell-mediated events as PMA was unable to activate progelatinase A in a cell-free system and that low dose tissue inhibitor of metalloproteinases-2, but not tissue inhibitor of metalloproteinases-1, totally inhibited PMA-induced activation; (c) was accompanied by an increase in the membrane-type matrix metalloproteinase (MT-MMP). We also found that the combination of PMA and the cytokine tumor necrosis factor-alpha increased HUVEC secretion and activation of gelatinase B. In conclusion, our data show that PMA activation of vascular endothelial cell progelatinase A is a cell membrane event that is at least partially mediated through a PKC-dependent mechanism and is accompanied by an increase synthesis of MT-MMP. These data suggest a role for MT-MMP in the activation of progelatinase A in vascular endothelial cells.
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PMID:Activation of human umbilical vein endothelial cell progelatinase A by phorbol myristate acetate: a protein kinase C-dependent mechanism involving a membrane-type matrix metalloproteinase. 878 Jan 71

In neurodegenerative disease or after brain injury, parenchymal cells in the central nervous system are activated to produce inflammatory mediators, mainly consisting of cytokine-induced factors, in a manner similar to, but clearly different from a peripheral inflammatory response. The upregulated expression of several extracellular matrix proteins in astrocytes located surrounding a neuritic plaque in Alzheimer's disease is a good example of such a response. A family of mediators which is cytokine-induced during an inflammatory response in the periphery are the matrix metalloproteinases. Matrix metalloproteinases are calcium-requiring, zinc-containing endopeptidases that constitute a major component of the enzyme cascade responsible for degradation of extracellular matrix proteins such as collagen, proteoglycan and laminin. Little is known about the cellular source or the function of matrix metalloproteinases in the central nervous system or how their expression is regulated in brain. Thus, it was of interest to determine which factors of the so-called 'brain inflammatory response' regulate the expression of these proteases in the nervous system. To this end, we measured the expression of matrix metalloproteinases in cultured rat astrocytes and microglia after treatment with various cytokines. Interleukin-1 beta, tumor necrosis factor-alpha and lipopolysaccharide were potent stimulators of matrix metalloproteinase-2 (gelatinase A) and matrix metalloproteinase-9 (gelatinase B) in cultured rat astrocytes; the effect of each secretagogue was inhibited in the presence of glucocorticoid. Interleukin-1 beta and lipopolysaccharide also stimulated the production of matrix metalloproteinase-3 (stromelysin-1) in astrocytes. In addition, activated microglia release matrix metalloproteinase-9. The 'coactivator' of monocytic phagocytes, interferon-gamma, rather than augmenting the response to lipopolysaccharide, inhibited it. Thus, cytokines appear to be potent regulators of matrix metalloproteinase production in astrocytes and microglia. The presence of these enzymes in 'inflamed' central nervous system may suggest their involvement in the pathogenesis or progression of neurodegenerative diseases which are associated with an inflammatory component. Much remains to be learned about the potential substrates for these enzymes and the mechanism of their activation in the central nervous system.
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PMID:Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. 894 20

Injury to a peripheral nerve is followed by a remodeling process consisting of axonal degeneration and regeneration. It is not known how Schwann cell-derived basement membrane is preserved after injury or what role matrix metalloproteinases (MMPs) and their inhibitors play in axonal degeneration and regeneration. We showed that the MMPs gelatinase B (MMP-9), stromelysin-1 (MMP-3), and the tissue inhibitor of MMPs (TIMP)-1 were induced in crush and distal segments of mouse sciatic nerve after injury. TIMP-1 inhibitor activity was present in excess of proteinase activity in extracts of injured nerve. TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro. In vivo, during the early phase (1 d after crush) and later phase (4 d after crush) after injury, induction of TNF-alpha and TGF-beta 1 mRNAs, known modulators of TIMP-1 expression, were paralleled by an upregulation of TIMP-1 and gelatinase B mRNAs. At 4 days after injury, TIMP-1, gelatinase B, and TNF-alpha mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages. TIMP-1 and cytokine mRNA expression was upregulated in undamaged nerve explants incubated with medium conditioned by macrophages or containing the cytokines TGF-beta 1, TNF-alpha, and IL-1 alpha. These results show that TIMP-1 may protect basement membrane from uncontrolled degradation after injury and that cytokines produced by macrophages may participate in the regulation of TIMP-1 levels during nerve repair.
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PMID:Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of metalloproteinases-1. 897 86

Scleritis is a sight-threatening inflammatory disorder of the eye characterized by the degradation of scleral matrix. Matrix metalloproteinases (MMPs) are ubiquitous proteolytic enzymes important in physiological and pathological processes, the activity of which is stringently controlled by the action of a family of natural antagonists, the tissue inhibitors of matrix metalloproteinases (TIMPs). We hypothesized that enhanced expression of MMPs, without the negative regulatory influence of TIMPs, may be a key feature of tissue destruction in inflammatory eye diseases, such as scleritis. The aim of this study was to localize and characterize cells expressing MMPs and TIMPs in sclera affected by necrotizing scleritis and, in a parallel study, to establish whether cytokines modulate MMP expression in cultured human scleral fibroblasts. In situ hybridization and immunohistochemical analyses indicated that resident scleral fibroblasts as well as inflammatory cells such as macrophages and T lymphocytes express stromelysin, gelatinase B, and TIMP-1 in necrotizing scleritis tissue. In addition, cytoplasmic immunoreactivity for tumor necrosis factor-alpha, an inducer of MMPs, was detected in infiltrating inflammatory cells. Cultured scleral fibroblasts stimulated with the combination of interleukin-1 alpha plus tumor necrosis factor-alpha increased TIMP-1 mRNA twofold above constitutive levels. By contrast, these cytokines induced a sevenfold increase in the steady-state levels of stromelysin mRNA. Using Western blotting, stromelysin and TIMP-1 protein production paralleled mRNA induction in cytokine-stimulated human scleral fibroblasts. Culture supernatants harvested from cytokine-stimulated human scleral fibroblasts were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis gelatin substrate zymography. Our results revealed a prominent 92-kd gelatinolytic band corresponding to gelatinase B, which was inducible with interleukin-1 alpha. These data provide evidence for our hypothesis, that an imbalance between enzyme/inhibitor ratios may be the underlying mechanism of the tissue destruction characteristic of scleritis. Our results demonstrate the potential involvement of MMPs and their modulation by cytokines produced by infiltrating inflammatory cells in destructive ocular inflammation.
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PMID:Increased expression of matrix metalloproteinases in vivo in scleritis tissue and in vitro in cultured human scleral fibroblasts. 903 78


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