Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q99542 (matrix metalloproteinase)
 15,999 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and immunomodulatory cytokine implicated in inflammatory conditions such as rheumatoid arthritis, Crohn's disease, multiple sclerosis and the cachexia associated with cancer or human immunodeficiency virus infection. TNF-alpha is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine. The processing enzyme(s) which cleave TNF-alpha are unknown. Here we show that the release of mature TNF-alpha from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-alpha into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-alpha precursor is cleaved to biologically active, mature TNF-alpha by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-alpha precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-alpha production.
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PMID:Processing of tumour necrosis factor-alpha precursor by metalloproteinases. 805 10

Treatment with interferon beta-1b has substantial clinical benefit in the demyelinating disease multiple sclerosis, yet the mechanism of action in the disease remains largely unknown. Gelatinase A (matrix metalloproteinase-2, 72-kd gelatinase) and B (matrix metalloproteinase-9, 92-kd gelatinase) are matrix metalloproteinases capable of enzymatic digestion of subendothelial basement membrane constituents. In human T cells, interleukin-2 induces gelatinase secretion and enhances gelatinase-dependent migration across an artificial basement membrane-like layer in vitro. Pretreatment of T cells with interferon beta-1b for 48 hours decreased interleukin-2-induced gelatinase production and secretion as determined by zymography. In parallel to the downregulation of gelatinase secretion, pretreatment with interferon beta-1b inhibited T-cell migration across the basement membrane in vitro by up to 90%, but had only a minor impact on cell locomotion per se. For both gelatinase secretion and T-cell migration, the inhibitory effect mediated by exposure to interferon beta-1b was dose dependent. Fluorescence-activated cell sorter analysis also showed that interferon beta-1b downregulates the interleukin-2 receptor alpha-chain and lowered the affinity of interleukin-2 to the cell surface by 30%, which may represent an additional mechanism for the observed effects of interferon beta-1b. The dramatic effects of interferon beta-1b on gelatinase expression and migration raise the possibility that its beneficial effects in multiple sclerosis may result from interference with the capacity of activated T cells to traverse the basement membrane and migrate to the central nervous system.
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PMID:Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. 900 89

In multiple sclerosis (MS), the influx of activated T lymphocytes into the brain parenchyma leads to the subsequent damage of oligodendrocytes, the cells that produce central nervous system (CNS) myelin. We report here that interferon beta-1b (IFNbeta-1b), a drug shown to be efficacious in the treatment of patients with MS, decreases the in vitro migration of activated T lymphocytes through fibronectin (FN), a major component of the basement membrane that surrounds cerebral endothelium. At 1,000 IU/ml, IFNbeta-1b reduced the migratory rate to that of unactivated T cells. In contrast, IFNgamma at 1,000 IU/ml, which caused a similar decrease (25%) in the proliferation rate of T lymphocytes as IFNbeta-1b, did not affect migration. All T-lymphocyte subsets and natural killer (NK) cells were demonstrated by flow cytometry to be equally affected by IFNbeta-1b treatment. 125I-Western blot analyses revealed that IFNbeta-1b treatment resulted in a marked reduction of the ability of T cells to cleave FN. The substrate-degrading capability of T lymphocytes was shown to be due predominantly to the activity of a 92-kd matrix metalloproteinase, MMP-9, whose levels were decreased by IFNbeta-1b. We suggest that the clinical benefits of IFNbeta-1b treatment in MS patients may be in part a result of the ability of this drug to significantly decrease MMP-9 activity, leading to a reduction of T-lymphocyte infiltration into the CNS.
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PMID:Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. 900 90

The matrix metalloproteinases (MMPs) are a family of at least 14 zinc-dependent enzymes which are known to degrade the protein components of extracellular matrix. In addition, MMPs and related enzymes can also process a number of cell surface cytokines, receptors, and other soluble proteins. In particular we have shown that the release of the pro-inflammatory cytokine, tumor necrosis factor-alpha, from its membrane-bound precursor is an MMP-dependent process. MMPs are expressed by the inflammatory cells which are associated with CNS lesions in animal models of multiple sclerosis (MS) and in tissue from patients with the disease. MMP expression will contribute to the tissue destruction and inflammation in MS. Drugs which inhibit MMP activity are effective in animal models of MS and may prove to be useful therapies in the clinic.
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PMID:Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. 904 8

The demyelination process that occurs in the central nervous system of patients with multiple sclerosis (MS) is, in part, due to an inflammatory response in which CD4+ and CD8+ T cells and macrophages infiltrate white matter. Although many studies have characterized myelin protein-specific CD4+ T cells, we have demonstrated that CD8+ CTL specific for myelin peptides can be identified. In the present study, the potential roles of these CD8+ CTL in the generation of the inflammatory responses associated with MS have been investigated by measuring the capacity of these T cells to secrete the following proinflammatory chemokines: macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta, lymphocyte chemoattractant factor (IL-16), IFN-inducible protein-10, as well as the proinflammatory enzymes of the matrix metalloproteinase family. The CD8+ CTL lines tested are derived from MS patients and are specific for two different myelin proteolipid protein-derived peptides presented by HLA-A2 and HLA-A3. All of the 17 CD8+ CTL lines secreted detectable amounts of MIP-1alpha and MIP-1beta. Nine of twelve CTL lines tested secreted IL-16, 10 of 12 lines tested secreted IFN-inducible protein-10, and 14 of 16 lines tested secreted matrix metalloproteinase-9. Collectively, these results indicate that myelin proteolipid protein peptide-specific CD8+ CTL may be an important source of proinflammatory soluble mediators that could promote and mediate the inflammatory response in MS demyelination.
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PMID:Chemokine and matrix metalloproteinase secretion by myelin proteolipid protein-specific CD8+ T cells: potential roles in inflammation. 912 Feb 56

The increased migration of peripheral blood mononuclear cells (PBMNCs) across a fibronectin (FN) matrix in response to the chemokines RANTES, MIP-1 alpha and MCP-1 is antagonized by interferon-beta-1b (IFN beta-1b). MCP-1 treatment of PBMNCs elevates their mRNA level and secretion of a matrix degrading enzyme, matrix metalloproteinase (MMP)-9, which is abrogated by IFN beta-1b. The clinical benefits of IFN beta-1b treatment in multiple sclerosis patients may in part be a result of this drug's ability to decrease the migration of PBMNCs in spite of a chemotactic gradient. Furthermore, the elevation of MMP-9 production by PBMNCs may be an important mechanism of action of chemokines.
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PMID:Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9. 941 58

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.
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PMID:Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. 966 91

The family of proteins called matrix metalloproteinases (MMPs) are a class of structurally related proteins that are collectively responsible for the metabolism of extracellular matrix proteins. These zinc and calcium dependent enzymes, which include the collagenases, stromelysins and gelatinases, are involved in normal tissue remodelling processes such as wound healing, pregnancy and angiogenesis. Under physiological conditions, in addition to the regulated proteolyses of inactive precursors to the active form, the degradative nature of these enzymes are precisely controlled by endogenous inhibitors (TIMPs). The excess syntheses and production of these proteins lead to the accelerated matrix degradation associated with diseases such as arthritis, cancer and multiple sclerosis. The MMPs have therefore proved to be attractive targets for structure based drug design. The pursuit of low molecular weight inhibitors of these proteins have encouraged structural studies on several members of family, so that the molecular details of enzyme-inhibitor interactions of the MMPs have become available. These studies provide insights into the basic structural framework of the MMP superfamily and reveal characteristics which promote specificity between individual members. The analyses of the three dimensional structure of the MMPs in the context of their primary sequence and the design and selectivity of low molecular weight inhibitors of the superfamily is the subject of this review.
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PMID:Matrix metalloproteases: variations on a theme. 978 58

Previous studies have suggested that surface expression of alpha4 integrin by autoreactive T-cell clones is necessary for the clones to induce experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. To provide direct evidence for this phenomenon, we have transfected alpha4 integrin into C19alpha4-LO, a myelin basic protein-reactive T-cell clone that does not express alpha4 integrin and does not induce EAE when adoptively transferred into a susceptible mouse strain. Transfection of alpha4 integrin converted this clone to an alpha4 integrin-expressing clone that induced EAE. We then examined potential mechanisms by which alpha4 integrin may facilitate the disease process. C19 T-cell clones adhered equally to a monolayer of microvascular endothelial cells, regardless of level of alpha4 integrin expression. However, in contrast to T-cell clones that do not express alpha4 integrin, T-cell clones that express alpha4 integrin (endogenously or by transfection) transmigrated through an endothelial cell layer and subendothelial matrix at an enhanced rate and adhered to recombinant vascular cell adhesion molecule-1 (rVCAM-1) and the CS1 fragment of fibronectin, and after adhesion to these ligands, a matrix-degrading metalloproteinase (MMP-2) was induced and activated. The clones were also shown to constitutively express the membrane-type matrix metalloproteinase (MT1-MMP), an enzyme that activates MMP-2. GM6001 and UK-221,316, inhibitors of metalloproteinases, reduced alpha4 integrin-mediated transmigration and EAE induction by C19 T-cell clones. In addition, we studied a second EAE-inducing T-cell clone, MM4, which constitutively expresses alpha4 integrin and MMP-2. Engagement of alpha4 integrin on the MM4 clone up-regulated the expression and activation of MMP-2, without changing the expression of MT1-MMP. MMP inhibitors also reduced transmigration of and EAE induction by the MM4 T-cell clone. These studies demonstrate directly that expression of alpha4 integrin by autoreactive T-cell clones is required for adoptive transfer of EAE in this model. We also define a role for alpha4 integrin in the disease process in mediating the induction and coordinate activation of a matrix metalloproteinase (MMP-2), which facilitates T-cell transmigration.
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PMID:The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the pathogenesis of experimental autoimmune encephalomyelitis. 984 Jun 19

The role of extracellular proteolysis in inflammatory demyelination, originally hypothesized as a mechanism for myelin degradation, is increasingly recognized as a pathogenetic step and as a target for therapy in human demyelinating disease. The activation of ubiquitous plasminogen by urokinase (u-PA) and tissue-type plasminogen activator (t-PA), which is associated with various neuropathologies, including multiple sclerosis (MS), is the key initiator of the activation cascade of the four classes of matrix metalloproteinases (MMPs): collagenases, stromelysins, membrane-type metalloproteinases and gelatinases. Spatiotemporal protein and mRNA expression of gelatinase B (MMP-9) and matrilysin (MMP-7) have been documented respectively in MS lesions and in the central nervous system (CNS) of animals developing experimental autoimmune encephalomyelitis (EAE). A close interaction between disease-promoting cytokines and extracellularly acting proteases is deduced from in vitro experiments. Cytokines regulate the balance between the proteases and their respective specific inhibitors at the transcriptional level, while proteolysis is a reciprocal mechanism to enhance (by activation) or downmodulate (by degradation) the specific activities of cytokines. In acute inflammation the contribution of chemokines is hierarchically organised, interleukin-8 (IL-8) and related CXC-chemokines inducing a rapid influx of neutrophils in the acute lesions and an instantaneous exocytosis of gelatinase B granules. This results in sudden and extensive damage to the CNS. In chronic disease involving autoimmune processes CC-chemokines that act mainly on mononuclear cell types appear to be more strictly regulated. As MMPs modify matrix components, promoting extravasation of lymphocytes and monocytes/macrophages and have the potential to generate encephalitogenic peptides from myelin basic protein, novel treatments for demyelinating diseases may be predicted by specific inhibition of these enzymes. Here we review plasminogen activators and the MMP family, in the context of their role in CNS inflammation and demyelination and highlight studies in which intervention in these protease cascades are and may be used to treat demyelinating diseases.
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PMID:Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. 1037 31


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