Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oral submucous fibrosis (OSF) is a chronic fibrotic disease of the oral cavity and oropharynx characterized by fibroelastic change in the mucosa which leads to progressive inability to open the mouth. The inflammatory cells in the lesional tissue consist mainly of T lymphocytes, with a high CD4:CD8 ratio, and major histocompatibility complex (MHC) class II expressing antigen-presenting cells. Cytokines and growth factors produced by inflammatory cells within the lesion may promote fibrosis by inducing proliferation of fibroblasts, upregulating collagen synthesis and downregulating collagenase production. The authors used a three-stage immunoperoxidase technique to investigate the expression of interleukin alpha (IL-1alpha) and beta, IL-6 interferon (IFN)-alpha, beta and gamma, transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in frozen sections of OSF and compared it with that in normal buccal mucosa. The expression of cytokines and growth factors in normal tissues was consistent with their well known distribution and cell of origin, but the intensity and distribution in OSF were all, with the exception of IFN-alpha and gamma, upregulated with strong expression in both the epithelium and underlying connective tissue. IFN-alpha showed a similar pattern of staining in both normal mucosa and OSF. IFN-gamma showed little or no expression in most lesional tissues, suggesting an innate deficiency or downregulation of this cytokine. The general increase in pro-inflammatory cytokines and growth factors, and reduced production of IFN-gamma, may play an important role in the pathogenesis of OSF.
 ...
PMID:Immunolocalization of cytokines and growth factors in oral submucous fibrosis. 977 Mar 33

Cytokines and growth factors regulate physiologic and pathologic turn-over of cartilage extracellular matrix (ECM) by altering the balance between tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs). Oncostatin M (OSM) is a cytokine of the IL-6 family whose levels are increased in the serum and synovial fluids of patients with rheumatoid arthritis. We examined responsiveness of the TIMP-3 gene to OSM in articular chondrocytes and studied the regulatory and signaling mechanisms of this response. OSM induced TIMP-3 mRNA and protein expression in a dose- and time-dependent fashion. Concomitantly, stromelysin-1 and collagenase-1 RNA and activities were also induced. A cartilage matrix growth factor, TGF-beta, induced TIMP-3, but combined OSM and TGF-beta did not further increase the extent of induction, suggesting a lack of synergy between the two. OSM induction of TIMP-3 gene expression was dependent upon de novo protein synthesis and transcription. RNA decay time-courses suggested that the OSM-mediated increase of TIMP-3 RNA was not due to enhanced message stability and, along with inhibition by actinomycin-D, suggested a transcriptional control. The antiinflammatory glucocorticoid, dexamethasone, down-regulated this augmentation. Investigation of the signaling mechanisms revealed that protein tyrosine kinase inhibitors genistein and herbimycin A, as well as the specific mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059, suppressed OSM-induced TIMP-3 message expression, suggesting the involvement of tyrosine kinases and mitogen-activated protein kinase cascades in the signaling of OSM leading to TIMP-3 RNA enhancement. Thus OSM can potentially alter the cartilage matrix metabolism by regulating genes like TIMP-3 and matrix metalloproteinases.
 ...
PMID:Oncostatin M up-regulates tissue inhibitor of metalloproteinases-3 gene expression in articular chondrocytes via de novo transcription, protein synthesis, and tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms. 979 37

One of the primary antioxidant enzymes, manganese-containing superoxide dismutase (MnSOD), has shown the ability to reverse malignant phenotypes in a variety of human tumor cells that are low or absent in MnSOD expression. We have observed that overexpression of human MnSOD in human breast cancer MCF-7 cells inhibits tumor growth both in vitro and in vivo. The signaling pathway underlying the MnSOD induced tumor suppression is unknown. We demonstrate here that transcriptional and DNA binding ability of AP-1 and NF-kappaB, but not SP-1, were inhibited (by 50%) in the MCF-7 cell line overexpressing MnSOD. When transiently expressing, MnSOD inhibited AP-1 but increased NF-kappaB transactivation, which can be abolished by sodium pyruvate, a hydrogen peroxide scavenger. To analyze the target genes responsible for MnSOD-induced tumor suppression, genes related to tumor growth and responsive to AP-1 or NF-kappaB were analyzed. AP-1 responsive collagenase I, stromelysin I, and NF-kappaB responsive IL-1 and IL-6 were down-regulated in the MnSOD stable transfectants compared to the control cell lines. Since TPA induces differentiation in human breast cancer cells and up-regulates MnSOD gene in HeLa cells, MnSOD expression and AP-1 and NF-kappaB activity were measured under TPA treatment. The results showed that TPA induced endogenous MnSOD expression and inhibited both AP-1 and NF-kappaB. Together, these results suggest that tumor suppression by overexpressing MnSOD is related to a modulation of AP-1 and NF-kappaB, which causes a down-regulation of genes responsible for tumor malignant phenotype.
 ...
PMID:Inhibition of AP-1 and NF-kappaB by manganese-containing superoxide dismutase in human breast cancer cells. 983 61

Two inflammatory vascular diseases often show multinucleated macrophages: Takayasu's disease and Horton's disease. Takayasu's disease is a segmentary panarteritis most prominent in the adventitia. Lesions show an inflammatory infiltrate close to the external elastic lamina. Progressive stenosis of the artery, sometimes complicated by calcifying atheroma is the typical course. Horton's disease or temporal arteritis is another segmentary arteritis. Lesions show a mixed inflammatory infiltrate partly localized in the adventitia where there are T CD4+ lymphocytes secreting II-2 and IFN-gamma and also macrophages expressing TGF beta 1, IL-6 and IL-1 beta, and partly situated in the interior part of the wall, around the internal elastic lamina, and mostly made of macrophages and giant cells which produce TNF, collagenase and nitric oxide that are responsible for destruction of the wall. The variety and subtleness of some lesions do not always make a precise diagnosis possible. But any inflammatory vascular lesion, even slight, can reveal a systemic vasculitis.
 ...
PMID:[Pathology of giant cell arteritis]. 992 94

The serum amyloid A (SAA) protein has been implicated in the progression and pathogenesis of rheumatoid arthritis through induction of collagenase activity in synovial fibroblast cells that line the joint tissues. We demonstrate that SAA is synergistically induced in synovial cells by interleukin (IL)-1 and IL-6 that are present at significantly high level in the synovial fluid of arthritis patients. These cytokines induced phenotypic changes in synovial cells, promoting protrusion and increased cellular contact. Induction of SAA under this condition is mediated by promoter elements located between -254 and -226, which contains binding sites for transcription factors Sp1 and SAA activating sequence binding factor (SAF). Mutation of these sequences abolishes SAA promoter response to IL-1 and IL-6. The role of Sp1 in SAA induction was demonstrated by increased DNA binding activity, phosphorylation, and increased protein content of Sp1 during cytokine treatment. Sp1 interacts with the SAA promoter in association with SAF as an SAF. Sp1 heteromeric complex. Furthermore, using a phosphatase inhibitor, we demonstrated increased transactivation potential of both Sp1 and SAF as a consequence of a phosphorylation event. These results provide first evidence for cytokine-mediated activation of Sp1 in synovial fibroblast cells and its participation in regulating SAA expression by acting in conjunction with SAF.
 ...
PMID:Activation of Sp1 and its functional co-operation with serum amyloid A-activating sequence binding factor in synoviocyte cells trigger synergistic action of interleukin-1 and interleukin-6 in serum amyloid A gene expression. 993 31

Evidence suggests that in the lower uterine segment at term an increased production of tumor necrosis factor (TNF) alpha and interleukin (IL)-1 beta induces an increase in the expression of adhesion molecules by the endothelium. The expression of endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 were found to increase from a cervical dilatation of 2-3 cm and reaches a maximum at cervical dilatation of more than 6 cm. Increased adhesiveness of the endothelium leads to extravasation of neutrophils into the cervical stroma. The chemotaxis and degranulation of these cells is triggered by a rise in the concentration of IL-8 found in the lower uterine segment when cervical dilatation progresses. A significant increase in stroma invasion by neutrophils with progressive cervical dilatation was observed. This finding coincides with a rise in the granulocytic matrix metalloproteinases (MMP)-8 and MMP-9 concentrations up to complete cervical dilatation. We found similar patterns of cytokine concentrations in the lower uterine segment of patients with preterm delivery: at 2-3 cm dilatation the concentrations of IL-1 beta, IL-6- und IL-8 were significantly higher than at less than 2 cm. Concomitantly, we also found an increase in MMP-8, MMP-9 and tissue inhibitor of metalloproteinases-1 concentrations from less than 2 cm to 2-3 cm cervical dilatation. These findings suggest that the changes in the lower uterine segment during preterm parturition seem to be similar to those at term and both resemble an inflammatory process.
 ...
PMID:The importance of extracellular matrix in the induction of preterm delivery. 1022 99

Interleukin-1 has been shown to contribute to infection-induced inflammatory processes during pregnancy. Prior work from this laboratory has demonstrated that serotonin-induced IL-1alpha also is required for the in-vitro production of collagenase in uterine smooth muscle cells, a normal, non-inflammatory process that occurs in-vivo during post-partum uterine involution. To understand the molecular mechanisms that regulate transcription of the IL-1alpha gene in these cells, we isolated and characterized 1.6 kilobases of the 5'-flanking region of the rat IL-1alpha gene. Sequencing and primer extension identified a single transcription start site and multiple potential regulatory elements, including a TATA box at - 30 bp, a CAAT box at - 74 bp, and a conserved AP-1 site at - 9 bp. This 5'-flanking DNA exhibited low basal promoter activity that was inducible by serotonin. Serotonin-induced promoter activity was unaffected or induced by either medroxyprogesterone or IL-1 receptor antagonist. This occurred despite the ability of both of these hormones to markedly decrease IL-1alpha mRNA. Deletional analysis revealed a strong repressor in the region between - 147 and - 98 bp; removal of this sequence resulted in a fivefold higher basal promoter activity that was still serotonin responsive. Constitutive promoter activity appeared to reside between - 97 and - 22 bp. Deletion of this promoter region, which contained the TATA and CAAT boxes and an NF-IL-6/PEA-3 site, resulted in decreased basal transcriptional activity to the low level seen in larger constructs. Mutational analysis showed that serotonin-inducible transcriptional activity was mediated, at least in part, by the conserved AP-1 site at - 9 bp. This site is located within a larger extended palindromic region: 5'-AAGCCTGACTCAGACTT-3', that together effects both the basal and serotonin-inducible expression of the IL-1alpha gene.
 ...
PMID:Serotonin-inducible transcription of interleukin-1alpha in uterine smooth muscle cells requires an AP-1 site: cloning and partial characterization of the rat IL-1alpha promoter. 1043 20

It is well documented that glucocorticoid excess causes bone loss, but the mechanisms of these effects remain poorly defined. To understand further the mechanisms of glucocorticoid-induced osteoporosis, we investigated the effects of glucocorticoids on bone formation and bone resorption by examining the proliferation, functional activities, and cytokine secretion of cultured human bone marrow stromal cells (hBMSC). Treatment with dexamethasone for 24 h at the concentration of 10(-8) M significantly suppressed [(3)H]thymidine incorporation and further inhibition was observed with longer treatment (8 days) or higher concentration (10(-7) M). Alkaline phosphatase activity of hBMSC was markedly stimulated with addition of dexamethasone (10(-8) M), to 191 +/- 22% (after 4 days) and 317 +/- 46% (after 7 days) of control. Dexamethasone (10(-8) M) treatment for 48 h decreased the incorporation of [(3)H]proline into collagenase-digestible protein (CDP; 43.7+/-7.9% of control) and non-collagen protein (65.2+/-8.4% of control), with a greater effect on CDP. Northern blot analysis indicated that alpha1(I)-collagen mRNA level was decreased by dexamethasone to 27.6 +/- 9.0% of the control value after 1 day of exposure, and to 55.2 +/- 6.2% after 7 days. Dexamethasone markedly suppressed basal production of interleukin (IL)-6 and IL-11 and that stimulated by parathyroid hormone (PTH), IL-1alpha, or tumour necrosis factor-alpha in a dose-dependent manner. These results suggest that the glucocorticoid-induced bone loss is derived at least in part via inhibition of bone formation, which includes the suppression of osteoblast proliferation and collagen synthesis. As both basal and PTH-stimulated production of IL-6 and IL-11 are decreased by dexamethasone, the increased bone resorption observed in glucocorticoid-induced osteopenia does not appear to be mediated by IL-6 or IL-11.
 ...
PMID:Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss. 1046 28

We showed previously that human malignant non-Hodgkin's lymphomas (NHL) degrade extracellular matrix (ECM) components through the action of metalloproteinases and that elevated expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) correlated with a poor clinical outcome in patients with NHL. In the present study we sought to investigate whether there is any correlation between the expression of gelatinases (MMP-2 and MMP-9), TIMP-1, and the expression of cytokines and growth factors such as interleukin-1beta (IL-1beta), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGFbeta), and basic fibroblast growth factor (bFGF) in human NHL. In lymphoma tissues obtained from 32 patients, elevated expression of IL-6 correlated significantly with elevated messenger RNA (mRNA) levels of MMP-9, MMP-2, and TIMP-1. Moreover, in human lymphoid cell lines of B- and T-cell origin (Raji, Jurkat, and NC-37), IL-6 stimulated production of MMP-9 and MMP-2 but not TIMP-1. In the Matrigel invasion assay IL-6 significantly upregulated transmigration of Raji and Jurkat cells, which in turn was inhibited by recombinant human TIMP-1 and anti-MMP-9 and MMP-2 antibodies. We postulate that IL-6 may play a role in the clinical aggressiveness of human NHL by stimulating MMP production.
 ...
PMID:Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin's lymphomas. 1047 38

Lipoxins are a novel class of endogenous eicosanoid mediators that potently inhibit inflammatory events by signaling via specific receptors expressed on phagocytic cells. Animal models have shown that lipoxin A4 (LXA4) down-regulates inflammation in vivo. Here we demonstrate, for the first time, the expression of LXA4 receptors, and their up-regulation by IL-1 beta, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA4 abrogated IL-1 beta stimulation of SF in vitro. IL-1 beta induced the synthesis of IL-6, IL-8, and matrix metalloproteinases (MMP)-1 and -3. At nanomolar concentrations, LXA4 inhibited these IL-1 beta responses with reduction of IL-6 and IL-8 synthesis, by 45 +/- 7% and 75 +/- 11%, respectively, and prevented IL-1 beta-induced MMP-3 synthesis without significantly affecting MMP-1 levels. Furthermore, LXA4 induced a 2-fold increase of tissue inhibitor of metalloproteinase (TIMP)-1 and a approximately 3-fold increase of TIMP-2 protein levels. LXA4 inhibitory responses were dose dependent and were abrogated by pretreatment with LXA4 receptor antiserum. LXA4-induced changes of IL-6 and TIMP were accompanied by parallel changes in mRNA levels. These results indicate that LXA4 in activated SF inhibits the synthesis of inflammatory cytokines and MMP and stimulates TIMP production in vitro. These findings suggest that LXA4 may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of SF.
 ...
PMID:Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. 1067 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>