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)

It has been shown that tumour necrosis factor-alpha (TNF-alpha) induces the gene expression of collagenase and enhances the invasiveness of many cell types. However, we have previously demonstrated that interferon-gamma (IFN-gamma) induces the chemotactic response of cells and we have studied the in vitro effects of both cytokines on invasive migration using a human fibrosarcoma cell line (HT-1080). Invasive migration occurred with HT-1800 cells through a basement membrane equivalent (matrigel) and collagen type I gel. Pre-incubation of cells with increasing concentrations of IFN-gamma resulted in a dose-dependent reduction of this invasive migration. TNF-alpha considerably enhanced the invasiveness of HT-1080 cells and of fibroblasts. This effect could be significantly diminished by the pre-incubation of cells with IFN-gamma. Inhibition of invasiveness did not appear to be due to an altered binding to the barriers or altered collagenolytic activity of these cells, as shown by attachment and collagenase assays. These data support the concept that IFN-gamma can reduce the invasiveness of transformed cells which contributes to its in vivo anti-neoplastic effect.
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PMID:The effect of interferon-gamma on the invasiveness of HT-180 cells. 157 Dec 53

The effect of leukoregulin, a 50-kD lymphokine with unique antitumor properties, was studied in vitro on several fibroblast functions. Leukoregulin did not inhibit fibroblast proliferation, as measured by cell enumeration and [3H]thymidine incorporation, and had no cytotoxic effect in terms of increased membrane permeability detected by trypan blue exclusion, two of the major leukoregulin actions on tumor cells. Leukoregulin induced a dose-dependent decrease in collagen synthesis, demonstrated by decreased [3H]proline incorporation into collagenase-digestible protein, as early as 6 h after the addition of the lymphokine to human fibroblasts. Leukoregulin inhibited the synthesis of both type I and type III collagen, as measured by SDS-PAGE and by specific radioimmunoassay. Neutralizing antibodies to interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma failed to alter the effect of leukoregulin on collagen synthesis, attesting that leukoregulin action was not due to contamination by these cytokines. Inhibition of collagen synthesis occurred concomitantly with increased secretion of prostaglandin E2 and a transient rise in intracellular cyclic AMP content, peaking at 6 h. However, blocking prostaglandin synthesis with indomethacin did not counteract inhibition of collagen synthesis by leukoregulin, demonstrating independence of this action of leukoregulin from cyclooxygenase metabolites. Leukoregulin also stimulated glycosaminoglycan production in a dose-dependent manner, affecting the synthesis of hyaluronic acid as the major fibroblast-derived extracellular glycosaminoglycan. In addition, secretion of neutral proteases (collagenase, elastase, caseinase) was increased. These observations indicate that leukoregulin is able to regulate synthesis of molecules critical to the deposition of the extracellular matrix by nontransformed nonmalignant fibroblasts.
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PMID:Modulation of human dermal fibroblast extracellular matrix metabolism by the lymphokine leukoregulin. 164 5

The expression of collagenolytic activity by cells represents the rate-limiting step in the turnover of collagen during remodeling. The collagenase gene is transcriptionally activated in normal dermal or rheumatoid synovial fibroblasts by interleukin-1 beta (IL-1 beta), resulting in secretion of trypsin-activatable procollagenase measuring in the range of 2.0-5.0 units/10(6) cells/48 h in the 14C-fibril assay. The addition of interferon-gamma (IFN-gamma; 50-100 units/ml) inhibits the expression of collagenase activity by 45-80% in these cells. The IL-1 beta induction of procollagenase protein was not altered by IFN-gamma, as judged by Western blot analysis using a monoclonal antibody to collagenase and by gelatin zymography, and procollagenase mRNA was also unaltered, as assessed by Northern blot analysis. Because collagenolytic activity is also controlled by the quantity of tissue inhibitor of metalloproteinases present, its expression was examined by Western blot analysis using a polyclonal antibody to tissue inhibitor of metalloproteinases and by reverse gelatin zymography. Tissue inhibitor of metalloproteinase protein was found to be unaltered or slightly less abundant in conditioned media from cultures treated with IL-1 beta and IFN-gamma when compared with that from cultures treated with IL-1 beta alone. However, the expression of the metalloproteinase activator of procollagenase, stromelysin, was found to be significantly inhibited by the addition of IFN-gamma. Addition of purified activated stromelysin to these conditioned media completely reconstituted collagenolytic activity. These observations demonstrate in an intact system that stromelysin is a specific activator necessary for the development of collagenolytic activity. Despite stromelysin's lack of catalytic activity against collagen, its expression can serve as a control point in the regulation of collagenolysis.
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PMID:Stromelysin expression regulates collagenase activation in human fibroblasts. Dissociable control of two metalloproteinases by interferon-gamma. 166 Apr 74

The endothelial blood-brain barrier (BBB) has a critical role in controlling lymphocyte traffic into the central nervous system (CNS), both in physiological immunosurveillance, and in its pathological aberrations. The intercellular signals that possibly could induce lymphocytes to cross the BBB include immunogenic presentation of protein (auto-)antigens by BBB endothelia to circulating T lymphocytes. This concept has raised much, though controversial, attention. We approached this problem by analyzing in vitro immunospecific interactions between clonal rat T lymphocyte lines with syngeneic, stringently purified endothelial monolayer cultures from adult brain micro-vessels. The rat brain endothelia (RBE) were established from rat brain capillaries using double collagenase digestion, density gradient fractionation and selective cytolysis of contaminating pericytes by anti-Thy 1.1 antibodies and complement. Incubation with interferon-gamma in most of the brain-derived endothelial cells induced Ia-antigens in the cytoplasm and on the cell surface in some of the cells. Before the treatment, the cells were completely Ia-negative. Pericytes were unresponsive to IFN-gamma treatment. When confronted with syngeneic T cell lines specific for protein (auto-)antigens (e.g., ovalbumin and myelin basic protein, MBP), RBE were completely unable to induce antigen-specific proliferation of syngeneic T lymphocytes irrespective of pretreatment with IFN-gamma and of cell density. RBE were inert towards the T cells, and did not suppress T cell activation induced by other "professional" antigen presenting cells (APC) such as thymus-derived dendritic cells or macrophages. IFN-gamma-treated RBE were, however, susceptible to immunospecific T cell killing. They were lysed by MBP-specific T cells in the presence of the specific antigen or Con A. Antigen dependent lysis was restricted by the appropriate (MHC) class II product. We conclude that the interaction of brain endothelial cells with encephalitogenic T lymphocytes may involve recognition of antigen in the molecular context of relevant MHC products, but that this interaction per se is insufficient to initiate the full T cell activation program.
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PMID:Immune function of the blood-brain barrier: incomplete presentation of protein (auto-)antigens by rat brain microvascular endothelium in vitro. 169 29

Eicosanoids, lymphokines, and free radicals are known to participate in the pathogenesis of inflammation. Tumour necrosis factor (TNF), interleukin-1 and 6 (IL-1 and IL-6) and colony stimulating factor -1 (CSF-1) are secreted mainly by activated macrophages, whereas T-cells secrete IL-2, IL-3, IL-4 and interferon-gamma (IFN-gamma). In addition, activated macrophages and lymphocytes can also produce eicosanoids and free radicals which have potent pro-inflammatory actions. Eicosanoids, lymphokines, and free radicals can modulate the immune response, cell proliferation, stimulate collagenase and proteases secretion and induce bone resorption; events which are known to be associated with various collagen vascular diseases. On the other hand transforming growth factor-beta (TGF-beta) produced by synovial tissue, platelets and lymphocytes can inhibit collagenase production, suppress T-cell and NK-cell proliferation and activation and block free radical generation and seems to be of benefit in rheumatoid arthritis. Drugs such as cyclosporine, 1,25,dihydroxycholecalciferol and pentoxyfylline can block lymphokine and TNF production and thus, may inhibit the inflammatory process. Essential fatty acids, the precursors of eicosanoids, are suppressors of T-cell proliferation, IL-1, IL-2 and TNF production and have been shown to be of benefit in rheumatoid arthritis, systemic lupus erythematosus and glomerulonephritis. Thus, the interactions between essential fatty acids, eicosanoids, lymphokines, TGF-beta and free radicals suggest that new therapeutic strategies can be devised to modify the course of collagen vascular diseases.
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PMID:Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radicals: relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. 172 26

Pulmonary infiltrating lymphocytes (PIL) isolated directly from human lung were examined for their surface immune phenotype by monoclonal antibody staining and cytofluorimetry. In order to purify PIL, resected lungs were enzymatically digested with collagenase and DNase and subjected to density centrifugation and nylon-wool column separation. In some cases, CD4+ lymphocytes were further purified with alpha CD8 and complement. The majority of pulmonary lymphocytes were CD2+ (87 +/- 1%) and CD3+ (73 +/- 4%). Virtually all of the CD3+ PIL were Ti alpha beta+. Greater than 90% of both CD4+ or CD8+ PIL were CD45RO+ and CD45RA-, consistent with prior antigen sensitization in vivo. A subset of CD4+ PIL (34 +/- 4%) expressed Leu8, the human congener of the murine MEL-14 lymphocyte homing receptor, whereas most homologous CD4+ peripheral blood lymphocytes were Leu8+ (75 +/- 8; P less than 0.01). HLA-DR surface antigens were expressed by 45 +/- 5% of CD4+ PIL versus 9 +/- 1% of CD4+ peripheral blood lymphocytes (P less than 0.001). There was no significant difference in the percentage of low-affinity interleukin-2 (IL-2) receptor-positive CD4+ lymphocytes in lung and blood (9 +/- 3% versus 13 +/- 2%). Analysis of the DNA synthetic cell cycle showed that approximately 5% of blood CD4+ lymphocytes and approximately 25% of CD4+ PIL were in S/G2/M. Compared to homologous blood T cells, purified PIL displayed enhanced proliferative responses to IL-2 and diminished responses to the lectin phytohemagglutinin. Lectin-stimulated PIL showed greater secretion of interferon-gamma and IL-2 than did blood lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Most human pulmonary infiltrating lymphocytes display the surface immune phenotype and functional responses of sensitized T cells. 193 Oct 75

The production of collagenase by human articular chondrocytes in response to interleukin-1 beta is inhibited in a dose-dependent manner by interferon-gamma (1-1,000 units/ml). The analysis of culture medium samples by Western blotting and the measurement of levels of tissue inhibitor of metalloproteinases suggest that the decrease in measurable collagenase activity is primarily due to the inhibition of procollagenase production. These results provide evidence of a role for interferon-gamma in limiting connective tissue degradation.
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PMID:Inhibition of interleukin-1-induced collagenase production in human articular chondrocytes in vitro by recombinant human interferon-gamma. 217 7

The biological effects of tumor necrosis factor (TNF) include the enhancement of fibroblast proliferation, the secretion of collagenase and prostaglandin E2 (PGE2) by fibroblasts, and the resorption of bone and cartilage, suggesting a role for this cytokine in arthritic conditions. To investigate this, we measured the levels of TNF in synovial fluids and evaluated its secretion by synovial fluid mononuclear cells and tissues from patients with rheumatoid arthritis, osteoarthritis, and seronegative arthritis and normals. TNF was found to be secreted in all arthritic conditions but not in normals. The levels of TNF were highest in synovial fluid and correlated with interferon-gamma (IFN-gamma) levels but not PGE2. The production of TNF was stable in a single joint for 3 to 6 months. Using immunohistochemical staining, TNF was localized to mononuclear cells in the lining layer, sublining, and perivascular areas of synovial tissue. The secretion of TNF by rheumatoid synovial fluid mononuclear cells was inhibited by PGE2, while IFN-gamma enhanced its production in those cells which were spontaneously secreting TNF. Our data suggest that TNF may play a role in various arthritic diseases.
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PMID:Characteristics of tumor necrosis factor production in rheumatoid arthritis. 247 44

The effect of tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) on collagen metabolism by human diploid fibroblasts in confluent monolayer culture was examined. Recombinant TNF alpha reduced collagen mRNA levels 2-fold and stimulated collagenase mRNA levels 5-fold, while recombinant IFN gamma affected only collagen mRNA levels. The combination of TNF alpha (10 ng/ml) and IFN gamma (100 ng/ml) resulted in a much stronger (about 30-fold) reduction of collagen mRNA levels indicating that the two cytokines act synergistically. In contrast no such synergism was observed with respect to collagenase mRNA levels. The effect of TNF alpha and IFN gamma on collagen metabolism reported here indicates a complex interaction of different cytokines in the control of tissue remodeling that occurs during inflammation, repair, or atrophy.
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PMID:Synergistic effect of tumor necrosis factor-alpha and interferon-gamma on collagen synthesis of human skin fibroblasts in vitro. 253 36

Class II major histocompatibility complex (MHC) antigens have been demonstrated on the surface of thyroid epithelial cells (thyrocytes) from patients with autoimmune thyroid disease. The present study was designed to investigate how the expression of class II MHC antigens is involved in autoimmune processes in Graves' disease by studying cellular interactions among thyrocytes, lymphocytes within thyroid glands (TG), and peripheral blood (PB) lymphocytes. Thyrocytes were prepared by collagenase digestion, and T or non-T cells were separated by E-rosette formation. Thyrocytes were cocultured in the presence or absence of interferon-gamma, and the expression of HLA-DR antigens on cultured thyrocytes was examined by an indirect immunofluorescence method using monoclonal anti-HLA-DR antibody and monoclonal anti-HLA-DQ antibody. The cellular interactions were assessed as the proliferative response of T cells to autologous stimulators, such as thyrocytes or lymphocytes. Expression of HLA-DR antigens on thyrocytes after culture for 18 h in the absence of interferon-gamma was found in two thirds of the patients with Graves' disease studied (n = 18). Interferon-gamma induced and maintained the expression of HLA-DR antigens on thyrocytes. The percentages of HLA-DR+T cells were significantly higher among TG-T cells than among PB-T cells [32.6 +/- 12.4% (+/- SD) vs. 12.2 +/-5.0%; n = 18; P less than 0.01]. Thyrocytes from Graves' patients induced proliferation of both autologous PB-T cells and TG-T cells, and TG-T cells stimulated proliferation of autologous PB-T cells. In conclusion, interferon-gamma induces HLA-DR antigen expression on thyrocytes from patients with Graves' disease, and these cells induce proliferation of autologous T cells, which may, in turn, act on thyrocytes to perpetuate the process.
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PMID:Class II major histocompatibility complex antigen expression and cellular interactions in thyroid glands of Graves' disease. 308 70


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