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

Matrix metalloproteinase 9 (MMP-9/gelatinase B) has recently been proposed to participate in the destruction of articular cartilage. Here, we report that interleukin 1 (IL-1) enhances the production of the precursor of MMP-9 in rabbit articular chondrocytes in primary culture, and this IL-1-mediated production of proMMP-9 is greatly augmented by cyclooxygenase inhibitors such as diclofenac and indomethacin, whereas the constitutive production of proMMP-2 (progelatinase A) is not modulated by IL-1 and/or cyclooxygenase inhibitors. Exogenous prostaglandin (PG) E1 and PGE2 suppress the proMMP-9 production in a dose-dependent manner. Similar results are also obtained with cultured rabbit synoviocytes. These results provide the first evidence that PGE down-regulates the production of proMMP-9 in chondrocytes and synoviocytes. Thus, cyclooxygenase inhibitors probably exert undesirable catabolic actions on the maintenance of articular cartilage under inflammatory conditions.
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PMID:Cyclooxygenase inhibitors augment the production of pro-matrix metalloproteinase 9 (progelatinase B) in rabbit articular chondrocytes. 787 5

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

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.
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PMID:Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester. 828 80

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

Matrix metalloproteinases (MMPs) and interleukin 1 (IL-1) are implicated in inflammation and tissue destruction, where IL-1 is a potent stimulator of connective tissue cells to produce the extracellular matrix-degrading MMPs. Here, we report that IL-1beta, but not IL-1alpha, is degraded by MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B). This degradation was effectively blocked by tissue inhibitor of metalloproteinases (TIMP)-1. When IL-1beta was treated with MMPs it lost the ability to enhance the synthesis of prostaglandin E2 and pro-MMP-3 in human fibroblasts. The primary cleavage site of IL-1beta by MMP-2 was identified at the Glu25-Leu26 bond. These results suggest that IL-1beta stimulates connective tissue cells to produce MMPs, but activated MMPs in turn negatively regulate the activity of IL-1beta.
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PMID:Degradation of interleukin 1beta by matrix metalloproteinases. 866 97

We have examined the regulation of precursor of matrix metalloproteinase 9 (proMMP-9)/progelatinase B production by tumor necrosis factor alpha (TNFalpha) and interleukin 1alpha (IL-1alpha) using human uterine cervical fibroblasts. TNFalpha, but not IL-1alpha, induces the production of proMMP-9 in the cervical cells. IL-alpha, however, suppresses the TNFalpha-induced proMMP-9 production. 12-0-tetradecanoylphorbol 13-acetate (TPA) also stimulates the cervical cells to produce proMMP-9, and IL-1alpha synergistically enhances its production. TNFalpha-induced proMMP-9 production is not mediated by protein kinase C (PKC), whereas the effect of IL-1alpha is through PKC. By contrast, proMMP-3/prostromelysin 1 is up-regulated by TNFalpha or TPA in the presence of IL-1alpha, whose modulation is PKC-dependent. The suppressive effect of IL-1alpha on the TNFalpha-induced proMMP-9 production is a new biological effect of IL-1 on MMP production.
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PMID:Tumor necrosis factor alpha (TNFalpha) induces pro-matrix metalloproteinase 9 production in human uterine cervical fibroblasts but interleukin 1alpha antagonizes the inductive effect of TNFalpha. 877 98

Towards gene transfer-based therapies of renal glomerulonephritis, this study examines the feasibility of using a mesangial cell vector (J. Clin. Invest. 94, 497-505, 1994) engineered to secrete interleukin-1 receptor antagonist (IL-1ra). IL-1ra cDNA was introduced into cultured rat mesangial cells, and stably transfected vector cells were established. Compared to mock transfectants, the vector cells showed blunted expression of gelatinase B, stromelysin and monocyte chemoattractant protein-1 in response to IL-1 beta. The attenuated responses were transferable to untransfected cells by cross-feeding with vector cell-conditioned media. The vector cells were then delivered into the glomeruli of rats via the renal circulation. Compared to either unmodified or mock cell-containing glomeruli, the glomeruli transferred with vector cells showed repressed expression of gelatinase B in response to IL-1 beta. Transfer of vector cells thus conferred insensitivity to IL-1 on the glomerulus. This result indicates the feasibility of modifying glomerular microenvironment against certain pathogenic mediators via the ex vivo transfer of therapeutically-relevant genes to the glomerulus.
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PMID:Gene transfer of interleukin-1 receptor antagonist into the renal glomerulus via a mesangial cell vector. 883 5

Since the degradation of uterine cervical extracellular matrix is an essential process in cervical ripening and dilatation at term, we examined the effect of pregnancy on the level of pro-matrix metalloproteinase 9 (proMMP-9)/progelatinase B in the rabbit uterine cervix and its regulation in uterine cervical fibroblasts. Uterine cervices shortly before term parturition contained high levels of proMMP-9 compared with those of nonpregnant rabbits. Uterine cervical fibroblasts prepared from rabbits at 23 days of gestation did not produce proMMP-9; in contrast, interleukin (IL)-1 alpha, IL-1 beta, or phorbol 12-myristate 13-acetate (PMA) induced proMMP-9 production along with an increase of proMMP-9 mRNA, and the IL-1-mediated induction of proMMP-9 was synergistically enhanced by PMA. On the other hand, physiological concentrations of progesterone suppressed IL-1-and/or PMA-mediated production of proMMP-9 in a dose-dependent manner. This suppressive effect of progesterone on proMMP-9 production was accompanied by a decrease in matrix metalloproteinase 9 (MMP-9) mRNA, indicating that progesterone down-regulates the production of proMMP-9 at the transcriptional level. These results indicate that in the rabbit uterine cervix, IL-1 alpha and IL-1 beta are effective inducers of the proMMP-9 production, and progesterone is a physiological suppressor. Thus, MMP-9 and progesterone are very likely to play essential roles in cervical ripening and dilatation in the rabbit, and the production of MMP-9 in the cervix is finely regulated during pregnancy.
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PMID:Hormonal regulation of matrix metalloproteinase 9/gelatinase B gene expression in rabbit uterine cervical fibroblasts. 904 99

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) produced by monocytes are believed to be involved in the migration of these cells through the basement membrane and the ensuing destruction of connective tissue in chronic inflammatory lesions. Because monocytes encounter a variety of cytokines at these sites, we examined the effect of cytokines either alone or in combination on the production of monocyte MMPs and TIMP-1. TNF-alpha, granulocyte-macrophage-CSF (GM-CSF), or IL-1 beta when added individually enhanced the endogenous levels of 92-kDa gelatinase (MMP-9) and TIMP-1 but failed to induce interstitial collagenase (MMP-1). However, GM-CSF, when added with either TNF-alpha or IL-1 beta, induced MMP-1 and synergistically enhanced MMP-9 and TIMP-1. Th2 cytokines, such as IL-4, inhibited the induction of MMPs and TIMP-1 by TNF-alpha, GM-CSF, and IL-1. Cytokine stimulation of MMP-1 was due, at least in part, to an increase in the release of arachidonic acid and PG E2 (PGE2), because inhibition of MMP-1 by indomethacin could be reversed by exogenous PGE2. In contrast to MMP-1, cytokine stimulation of MMP-9 and TIMP-1 was unaffected by indomethacin. The PGE2-independent induction of monocyte MMP-9 and TIMP-1 by these cytokines differed from stimulation of MMP-9 and TIMP-1 by LPS, which is in large part PG-dependent. In addition, LPS stimulated higher levels of MMP-1 whereas cytokines induced higher levels of MMP-9 and TIMP-1. This is the first demonstration that monocyte MMP-1 can be induced by cytokines and that MMP-1, MMP-9, and TIMP-1 are differentially regulated by cytokines through PG-dependent and -independent mechanisms.
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PMID:Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin-dependent and -independent mechanisms. 974 73

Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.
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PMID:Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. 975 50


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