Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Islets from male B10.BR mice (H-2k) were isolated by the collagenase technique, hand-picked with a Pasteur pipette, and incubated in tissue culture media supplemented with recombinant murine interferon-gamma (rIFN-gamma), recombinant murine tumor necrosis factor (rTNF), or both. IAk-molecules could be identified on the surface of islets incubated for 5 days with a combination of rIFN-gamma (1, 10, or 100 ng/ml) and rTNF (10 or 50 U/ml) by indirect immunofluorescence. Optimal concentrations of rIFN-gamma and rTNF, 10 ng/ml and 50 U/ml, respectively, were used in all subsequent experiments. Weak Ia-positivity could be identified on the surface of islets cultured with both cytokines for as little as 48 hours; however, the staining appeared most intense after 5 days of culture. Intensely Ia-positive islets were then carefully washed and cultured in media without either cytokine; Ia positivity could be identified on the surface of these islets for up to 1 week. Dispersed islet cells were cultured with rIFN-gamma alone (10 ng/ml), rTNF alone (50 U/ml), or both cytokines for 5 or 10 days. After either 5 or 10 days of culture with both cytokines, intense immunofluorescent staining for Ia could be identified on the surface of greater than 80-90% of the viable islet cells. Culture with IFN alone for 10 days resulted in 15-20% Ia positivity; culture with TNF alone did not cause Ia expression.
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PMID:Tumor necrosis factor enhances interferon-induced Ia antigen expression on murine islet parenchymal cells. 312 60

Preterm delivery remains the preeminent problem in perinatal care worldwide. Recent data suggest that cervical/vaginal microflora, and/or the inflammatory responses they engender, produce factors which can cause or predispose to preterm labor and rupture of membranes. Microorganisms mediating such processes may not be "recognized pathogens" and are often considered normal flora. These microorganisms may act singly, additively, or synergistically with host factors released during an induced inflammatory response. Both qualitative and quantitative aspects of cervical/vaginal microflora are likely important. Multiple cervical/vaginal microorganisms produce IgA proteases, neuraminidases, and mucinases which may facilitate passage of these and other agents past cervical barriers and into the lower uterine segment. Multiple microflora also produce phospholipases A2 and C, each of which can locally augment production of eicosanoids within the uterus which are important in cervical ripening and labor. Similar microflora produce various proteases, including collagenase, which can focally weaken the amniochorion and predispose to premature rupture of membranes and cervical ripening. Intrauterine microorganisms induce inflammatory reaction and may engender local release of similar proteases, phospholipases, oxygen radicals, as well as platelet activating factor (PAF), and lymphokines which can also initiate or further potentiate labor-inducing mechanisms. Roles for uteroplacental or systemic release of tumor necrosis factor (TNF) and various interferons are beginning to be understood. Recognition of microbe-induced pathogenesis of some cases of preterm birth offers the hope of specific treatment and prophylaxis. In recent studies, administration of erythromycin and tocolytic agents was associated with an improved outcome in selected women. "Just why so many gravidas go into labor prematurely and hence give birth to infants who often are unable to cope with extrauterine conditions is one of the great unsolved problems of obstetrics."
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PMID:Preterm birth and infection: pathogenic possibilities. 328 11

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.
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PMID:Human vascular smooth muscle cell-monocyte interactions and metalloproteinase secretion in culture. 748 54

Nitric oxide is a highly reactive mediator released in the liver by hepatocytes, Kupffer cells and endothelial cells during endotoxin-induced inflammation. In this study we determined whether Ito cells also produce nitric oxide after exposure to endotoxin. For induction of endotoxemia, rats were injected intravenously with Escherichia coli lipopolysaccharide (2.5 mg/kg). Ito cells were isolated from the animals 48 hr later by means of in situ perfusion of the liver with protease and collagenase followed by purification on an arabinogalactan gradient. Ito cells from untreated and endotoxemic rats were found to produce low levels of nitric oxide in response to interferon-gamma. In both cell types, this response depended on L-arginine and was blocked by NG-monomethyl-L-arginine, a specific nitric oxide synthase inhibitor. Cells from rats treated with endotoxin produced significantly more nitric oxide than did cells from untreated animals; this was due, at least in part, to increased expression of protein for an inducible form of nitric oxide synthase. These cells also responded to stimulation with lipopolysaccharide in vitro, as well as the combination of interferon-gamma and lipopolysaccharide, which was synergistic in stimulating nitric oxide production. Tumor necrosis factor-alpha and macrophage colony-stimulating factor were also found to stimulate nitric oxide production by Ito cells from endotoxemic rats. In addition, in these cells, tumor necrosis factor-alpha synergized with interferon-gamma in inducing nitric oxide production. The combination of interferon-gamma and lipopolysaccharide was also found to inhibit Ito cell DNA synthesis, as measured on the basis of [3H]-thymidine uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of hepatic Ito cell nitric oxide production after acute endotoxemia. 752 4

Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, collectively termed the nitric oxide synthases. We investigated the role of NO. in the modulation of two metal-dependent proteolytic enzymes (collagenase and stromelysin) which are activated during inflammatory and infective arthritis. The inflammatory mediators interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and the bacterial cell wall fragment endotoxin, induced both nitric oxide synthase activity and stromelysin and collagenase activity in whole cell preparations and in conditioned media from explants of bovine and human cartilage. Both NO2- (the stable end-product of NO.) and metalloprotease activity were inhibited by competitive inhibitors of nitric oxide synthase. The NO. donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP) also induced metalloprotease activity in a dose-dependent fashion. These data provide evidence that NO. plays a regulatory role in the activation of metal-dependent proteases in articular chondrocytes and cartilage.
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PMID:Nitric oxide activates metalloprotease enzymes in articular cartilage. 752 96

The molecular basis by which transforming growth factor (TGF)-beta 1 protects certain tumor cells from tumor necrosis factor (TNF) cytotoxicity was investigated. When pretreated, with TGF-beta 1, -beta 2, and -beta 3, murine L929S fibroblasts developed resistance to TNF cytotoxicity. Time course experiments revealed that TGF-beta 1 initially induced both cellular protein-tyrosine phosphorylation and simultaneous secretion of a novel extracellular matrix TNF-resistance triggering (TRT) protein(s), which closely preceded the acquisition of TNF-resistance. TGF-beta 2 and -beta 3 also increased tyrosine phosphorylation. However, both molecules failed to stimulate TRT secretion. The increased levels of phosphorylation, particularly to 9 specific protein tyrosine kinase inhibitor-sensitive cellular proteins, appeared to alter the TNF killing pathway. TGF-beta 1-induced TRT secretion required participation of unknown serum factors. TRT adhered strongly to polystyrene plates and resisted treatment with heat (60 degrees C, 30 min), collagenase, alpha 2-macroglobulin, heparin, antibodies against TGF-beta s, and limited trypsin digestion. Notably, TRT promoted TNF-resistance via activation of tyrosine and serine/threonine kinase functions in L929S. Thus, the molecular pathway involves TGF-beta 1-mediated initiation of a rapid tyrosine phosphorylation of cellular protein substrates (which alters TNF cytotoxic pathway), and a simultaneous secretion of TRT, which in turn signals the cells to maintain the levels of phosphorylation, thereby sustaining the TNF-resistance.
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PMID:Transforming growth factor-beta 1 induction of novel extracellular matrix proteins that trigger resistance to tumor necrosis factor cytotoxicity in murine L929 fibroblasts. 753 77

Matrix metalloproteinases (MMPs) are a family of inducible enzymes that degrade extracellular matrix components, allowing cells to traverse connective tissue structures efficiently. Specific tissue inhibitors (TIMPs) function as physiologic inhibitors of MMP activity. Because neovascularization may require various proteinases, we characterized the profile of metalloenzyme production by microvascular endothelial cells (MEC) and the modulation of expression by phorbol esters (PMA) and by the physiologically relevant cytokines tumor necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor, and interferon-gamma. MMP expression by MEC and large-vessel human umbilical vein endothelial cells (HUVEC) was determined by enzyme-linked immunosorbent assay, immunoprecipitation, Northern hybridization, and transfection assays. Constitutive expression of MMPs by endothelial cells was low. PMA stimulated the production of collagenase, stromelysin, 92-kDa gelatinase, and TIMP-1 in both endothelial cell types. TIMP-2 was constitutively expressed by MEC and HUVEC, but was down-regulated by PMA. TNF-alpha induced an endothelial-cell-specific up-regulation of collagenase with a concomitant inhibition of PMA-induced TIMP-1 up-regulation, a response that is distinct from that of fibroblasts. Interferon-gamma up-regulated TIMP-1 production by MEC and blocked PMA and TNF-induced up-regulation of collagenase. Northern hybridization assays showed pretranslational control of PMA-, basic fibroblast growth factor-, and TNF-alpha-induced MMP expression. Collagenase-promoter CAT constructs containing 2.28 kb of the 5' region of the collagenase gene demonstrated transcriptional regulation. The potential physiologic relevance of such regulation was shown in an in vitro migration assay. MEC were stimulated to migrate by wounding and exposure to TNF-alpha. Collagenase mRNA was prominently expressed by the migrating cells, as shown by in situ hybridization. In sum, MEC have a unique profile of MMP expression and regulation compared with other cell types, which may be important for wound healing and angiogenesis, particularly during the early phase of migration.
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PMID:Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. 754 47

A method for the isolation and long-term culture of human microvessel endothelial cells from mammary adipose tissue (HuMMEC) obtained at breast reduction surgery has been developed. Pure cultures of HuMMEC were isolated by sequential digestion of the fat with collagenase and trypsin followed by specific selection of microvessel fragments with Ulex europaeus agglutinin-1 coated magnetic beads (Dynabeads). The resulting cells formed contact-inhibited monolayers on gelatin and fibronectin substrates and capillary-like "tubes" on Matrigel; they also expressed von Willebrand factor, angiotensin-converting enzyme, and accumulated acetylated low density lipoprotein. Further immunofluorescence characterization revealed the presence of antigens for the endothelial cell specific monoclonal antibodies EN4 and H4-7/33. In addition, the origin of these cells was confirmed by the demonstration of the cell adhesion molecules, platelet endothelial cell adhesion molecule-1 (CD31), and endothelial leukocyte adhesion molecule-1 (ELAM-1/E-selectin) upon stimulation with tumor necrosis factor (TNF) alpha. HuMMEC were found to express-1 ELAM-1 at lower levels of TNF alpha (< 10 ng/ml) than required by human umbilical vein endothelial cells. These cells should provide a useful in vitro model for studying various aspects of microvascular biology and pathology.
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PMID:Isolation and characterization of microvessel endothelial cells from human mammary adipose tissue. 768 48

This review considers the mechanisms controlling collagen deposition in mammalian lung in five different states: normal development, fibrosis, erosion, pneumonectomy, and the steady state. Deposition is the net result of positive and negative processes. The major positive processes are control of cell number and type, regulation of transcription and translation, post-translational modifications, fibril formation, and covalent cross-linking. The negative mechanisms are intracellular degradation, collagenase-mediated degradation, and phagocytosis, and they are integral to the life cycle of collagen. Cytokines and growth factors have many and complex effects on all the processes that constitute collagen metabolism. Interleukin-1 and tumor necrosis factor-alpha can either stimulate or inhibit collagen accumulation, presumably depending on the immediate environment. Interleukin-6 inhibits collagen degradation, and gamma-interferon inhibits collagen production. Platelet derived growth factor and fibroblast growth factor have powerful mitogenic effects on connective tissue cells in lung, and can also affect collagen production directly. Transforming growth factor-beta activates a battery of processes that uniformly contribute to accumulation of collagen. Transforming growth factor-beta may be the "master switch" for a fibrotic program in lung. Therapeutic approaches to controlling lung fibrosis by manipulating cytokine levels are promising. Prostaglandin E has uniformly negative effects on net collagen accumulation and may play a central role in an erosion program.
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PMID:Control of collagen deposition in mammalian lung. 777 Apr 62

The neutral metalloproteinase collagenase is known to be, among others, one of the key enzymes promoting joint destruction in patients with rheumatoid arthritis. Because inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-alpha, are considered to activate collagenase gene expression through activation of the transcription factor activator protein-1, we examined whether the water-soluble gold compound aurothiomalate (AuTM) influenced collagenase gene expression, using phorbol ester-treated human fibroblasts. However, AuTM did not prevent phorbol ester-mediated activation of activator protein-1 DNA-binding activity and subsequent induction of collagenase gene expression. In contrast, AuTM counteracted the repressive effects of glucocorticoids on collagenase gene expression and restored collagenase mRNA levels. The molecular target of this paradoxical AuTM action was suggested to be the glucocorticoid receptor.
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PMID:Paradoxical derepression of collagenase gene expression by the antirheumatic gold compound aurothiomalate. 780 28


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