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)

Hepatocyte growth factor (HGF) is known to have a number of biological properties including promoting tumor progression of human carcinomas. Metastasis involves a number of events that are attributed to induction by paracrine factors such as HGF. Identification of natural inhibitors of these events would allow better control of tumor progression. Recently we demonstrated that interleukin 4 (IL-4) can regulate proliferation of various human carcinoma cell lines. In the present study, we used established human colon carcinoma cell lines and primary colon carcinoma cell cultures to determine if IL-4 could regulate HGF-induced cell proliferation and other events of tumor progression such as MMP (matrix metalloproteinases)-1, -2, and -9 production, cell migration and cell-matrix invasive activity. All colon carcinoma cell lines expressed HGF and IL-4 receptors. IL-4 significantly inhibited HGF-induced proliferation of one cell line. Cell-matrix invasion was significantly enhanced by HGF (0.1-10 ng/ml); IL-4 (1-10 U/ml) significantly inhibited HGF-induced invasion in a dose-dependent manner. IL-4 also inhibited HGF-induced cell-matrix invasion of metastatic colon carcinoma cells and HGF-induced cell migration. HGF enhanced MMP-1, -2, and -9 production by cell lines. This effect could be inhibited by IL-4. These findings indicate that IL-4 is a potent inhibitor of HGF-induced invasion and metastasis-related functions of human colon carcinoma cells.
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PMID:Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomas. 889 90

Interleukin-1 (IL-1) in combination with other cytokines can induce a reproducible release of collagen fragments from bovine nasal cartilage in culture. Over 70% of the total collagen is released by day 14 and this release is accompanied by the appearance of collagenolytic activity in the medium that cleaves collagen specifically at the one quarter/three quarter position. Interleukin-4 is able to prevent the release of collagen fragments from the tissue and this is accompanied by a reduced secretion and activation of collagenase (MMP-1) with an increase in tissue inhibitor of metalloproteinases-1 (TIMP-1). IL-4, especially in the presence of IL-1, increased TIMP secretion by bovine nasal cartilage in culture. These results suggest that IL-4 is able to specifically block cartilage collagen resorption by down-regulating the production of collagenase (MMP-1) and up-regulating TIMP-1 by chondrocytes within the cartilage.
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PMID:Interleukin-4 blocks the release of collagen fragments from bovine nasal cartilage treated with cytokines. 898 76

The study of liver dendritic cells (DC) and their progenitors is restricted by the small numbers that can be isolated or propagated from normal hepatic tissue. We examined the ex vivo growth, phenotype, and function of these cells after the administration to mice of the recently cloned hemopoietic growth factor flt3 ligand (FL), which is highly effective in mobilizing stem/progenitor cells. FL treatment (10 microg/day for 10 days) resulted in a mean 14-fold increase in the absolute number of nonparenchymal cells recovered from collagenase-digested livers compared with the control value. Culture of these nonparenchymal cells in granulocyte-macrophage CSF (GM-CSF; 1000 U/ml) resulted in the early formation of proliferating cell clusters and maximal release (within 4-5 days) of markedly increased numbers of nonadherent, low buoyant density cells per liver. Maximal release of low buoyant density cells propagated from control livers was at the later time of 6 to 8 days. Cells from both sources were DEC-205+, CD11c+, MHC class II+, CD80(low) (i.e., low level of CD80), CD86(low) and CD40(low). This immature phenotype was linked to poor T cell allostimulatory activity, indicative of DC progenitors. Propagation of cells from livers of FL-treated mice in GM-CSF and IL-4 resulted in a more mature DC phenotype and function. Maturational changes were also observed following exposure of the GM-CSF-stimulated progenitors to type 1 collagen for 3 additional days. The ability of FL to boost production of large numbers of liver DC progenitors provides opportunities for the further study of these important APC in normal liver immunobiology and in immune-mediated hepatic disorders.
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PMID:In vivo administration of flt3 ligand markedly stimulates generation of dendritic cell progenitors from mouse liver. 937 22

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

Interleukin (IL)-13 has been implicated in the pathogenesis of various diseases characterized by fibrosis. We describe the effects of IL-13 on collagen homeostasis from normal (NF) and keloid (KF) fibroblasts and compare these effects with those of IL-4 and transforming growth factor (TGF)-beta(1). Total collagen generation was up-regulated in NF after 48 h of stimulation by IL-13; in KF, IL-13 stimulated a more rapid collagen response. The kinetics and magnitude of collagen generation induced by IL-13 were equivalent to those induced by similar concentrations of IL-4 and TGF-beta(1). Collagen type I production paralleled total collagen generation from both NF and KF; however, IL-4-induced collagen type I and total collagen production from KF was more transient than that induced by either IL-13 or TGF-beta(1). Procollagen 1alpha1 gene expression was induced in KF by stimulation with IL-13 for 24 h. Moreover, IL-13 was unique among these three cytokines in its ability to induce gene expression for procollagen 3alpha1. Finally, IL-13 inhibited IL-1beta-induced matrix metalloproteinase (MMP)-1 and MMP-3 production and enhanced tissue inhibitor of metalloproteinase (TIMP)-1 generation from NF; although similar effects were observed with IL-4, TGF-beta(1) transiently enhanced MMP-1 and MMP-3 generation without effecting TIMP-1. In KF, IL-13 and IL-4 inhibited MMP-3, whereas TGF-beta(1) enhanced MMP-3; TIMP-1 was unaffected by any of the three cytokines. These data demonstrate both the profibrotic effects of IL-13 on collagen homeostasis and the potential differential regulation of collagen homeostasis in fibroblast subtypes by IL-13.
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PMID:Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. 1068 14

Monocytes/macrophages are directly involved in tissue remodeling and tissue destruction through the release of matrix metalloproteinases (MMP). In the present study, we examined the effect mediated by contact of polarized Th cells with mononuclear phagocytes on the production of MMP-1, MMP-9, and their inhibitor. Plasma cell membranes from Ag-activated Th1 and Th2 cells were potent inducers of MMP-1 production by THP-1 cells. Cell membrane-associated TNF was found to be only partially involved in MMP-1 induction by both Th1 and Th2 cells. In Th2 cells exclusively, membrane-associated IL-4 induced MMP-1 production by THP-1 cells. This membrane-associated IL-4 effect was additive to that of TNF and was specifically observed on MMP-1 as MMP-9 production was concomitantly inhibited. Similarly, soluble IL-4 induced THP-1 cells to produce MMP-1, its effect proving additive to that of soluble TNF and to that of cell membranes of mitogen-activated HUT-78 cells. Its activity was blocked by IL-4 neutralization, and was unaffected by the presence of indomethacin. These effects on THP-1 cells were observed at protein and mRNA levels. Although inhibitory on freshly isolated peripheral blood monocytes, soluble IL-4 enhanced T cell-induced MMP-1 and inhibited MMP-9 production both at protein and mRNA levels in monocytes cultured for 7 days in the presence of GM-CSF. Thus, in contrast with previously reported effects, Th2 and IL-4 specifically induce MMP-1 production by mononuclear phagocytes at various stages of differentiation. This IL-4 activity may be relevant to pathological conditions dominated by Th2 inflammatory responses, resulting in tissue remodeling and destruction.
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PMID:Th2 cell membrane factors in association with IL-4 enhance matrix metalloproteinase-1 (MMP-1) while decreasing MMP-9 production by granulocyte-macrophage colony-stimulating factor-differentiated human monocytes. 1082 Feb 78

Interleukin (IL-)17 is a T cell-derived pro-inflammatory cytokine produced by RA synovium. We studied the role of IL-17 in the synovium cytokine network to determine whether it can influence the inflammatory and destructive pattern characteristic of RA. Herein, we investigated whether the production and action of MMP-1 and its inhibitor TIMP-1 could be modulated by IL-17 in the presence of pro-inflammatory cytokine (IL-1) and anti-inflammatory cytokines (IL-4, IL-13, IL-10). The effect of the blockade of endogenous IL-17 on the secretion of MMP-1 and TIMP-1 by RA synovium and matrix destruction was also studied. IL-17 increased the spontaneous production of MMP-1 by synoviocytes five-fold. IL-1 was more potent since it increased MMP-1 production nine-fold. Addition of IL-4, IL-13 and IL-10 to synoviocyte cultures reduced the spontaneous production of MMP-1 and induced TIMP-1 production by synoviocytes stimulated with IL-17 or/and IL-1beta. In the presence of anti-IL-17 blocking mAb, MMP-1 production and collagenase activity by RA synovium was reduced by 50% and associated with a 50% reduction in type I collagen C-telopeptide fragments (CTX) released in the supernatants, demonstrating the direct contribution of IL-17 in destruction. IL-17 and its producing T cells appear to contribute to the inflammatory process involved in the rheumatoid lesion.
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PMID:Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis. 1088 Feb 56

Loosening of a prosthesis is a major problem in total joint arthroplasty. To assess levels of cytokines in patients with such loosening, we measured the pseudosynovial fluid concentration of the following cytokines; tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-4, IL-6, IL-10, IL-12, matrix metalloproteinase (MMP)-1, and MMP-3. We examined the pseudosynovial fluid in patients with a loose hip prosthesis (group A; n = 8) and the synovial fluid in patients with osteoarthritis (OA) of the hip (group B; n = 18) using enzyme-linked immunosorbent assays. The mean concentration of IL-12 was significantly higher in group A than in group B (P < 0.01). Also, we found a significant (P < 0.05) correlation between the concentration of IL-12 and the concentration of MMP-1 in the patients with prosthesis loosening. The concentrations of TNF-alpha, IL-1beta, IL-4, IL-6, IL-10, IFN-gamma, MMP-1, and MMP-3 appeared to be similar in the two groups, although the small number of samples available precluded us from determining that there was no significant difference. The present study is the first to report elevated IL-12 levels in the pseudosynovial fluid of patients with a loose prosthesis. The immunoregulatory effect of IL-12 against wear particles could play an important role in causing loosening of the prosthesis.
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PMID:Elevated interleukin-12 in pseudosynovial fluid in patients with aseptic loosening of hip prosthesis. 1098 86

To assess the role of bone marrow in the pathogenesis of rheumatoid arthritis (RA), we examined the capacity of CD34(+) cells from bone marrow to generate fibroblast-like type B synoviocytes. CD34(+) cells from the bone marrow of 22 RA patients differentiated into cells with fibroblast-like morphology, which expressed prolyl 4-hydroxylase, in the presence of stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha), much more effectively than CD34(+) cells from bone marrow of 15 control subjects (10 patients with osteoarthritis and 5 healthy individuals). The generation of fibroblast-like cells was not at all observed in cultures with SCF, GM-CSF, and interleukin 4 (IL-4) with or without TNF-alpha. Generation of fibroblast-like cells was correlated with matrix metalloproteinase (MMP)-1 levels in culture supernatants. Thus, MMP-1 levels were significantly higher in TNF-alpha-stimulated cultures of bone marrow CD34(+) cells from patients with RA than in those from the control group. These results indicate that bone marrow CD34(+) cells from patients with RA have abnormal capacities to respond to TNF-alpha and to differentiate into fibroblast-like cells producing MMP-1, suggesting that bone marrow CD34(+) progenitor cells might generate type B synoviocytes and thus could play an important role in the pathogenesis of RA.
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PMID:Induction of fibroblast-like cells from CD34(+) progenitor cells of the bone marrow in rheumatoid arthritis. 1152 91

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.
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PMID:[New therapy developments in rheumatoid arthritis]. 1175 32


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