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)

Proteases and especially collagenase injected into the lateral brain ventricles of rats are able to increase the permeability of the blood-brain barrier to trypan blue. Treatment of the rats with anthocyanosides of Vaccinium myrtillis diminishes the permeability increasing effect of collagenase and accelerate the recovery of normal permeability. This effect seems to be related to a less effective enzymatic attack on collagen, as hydroxyproline content in the CSF is increased less after collagenase injection in treated animals than in untreated controls.
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PMID:Action of anthocyanosides of Vaccinium myrtillis on the permeability of the blood brain barrier. 20 5

Minced human tonsils were digested with DNase and collagenase, and lymphoid cell-depleted low density cells were cultured and grown in granulocyte-macrophage-CSF. Large, morphologically homogenous adherent cells with elongated extensions grew continuously in culture. These nonphagocytic cells appear to be related to follicular dendritic cell (FDC) as they do not have properties of monocytic lineage cells or dendritic cells and because, like FDC, 1) they express CD11b, CD14, CD29, CD40, CD54, CD73, CD74, and VCAM-1, and do not express CD11c, CD22, T cell markers, CD18, CD25 and CD45; and 2) they bind human B lymphocytes and B cell lines, but not T lymphocytes by an adhesion blocked in part by mAb to VLA-4 (CD49d). The cultured FDC also augmented B cell proliferation stimulated by anti-mu sera and/or CD40 mAb. Cultured FDC spontaneously produced low levels of IL-6, but did not produce IL-1 alpha or TNF-alpha; however, after treatment with either IFN-gamma or LPS, they produced more IL-6. The expression of CD54 (ICAM-1) was elevated by treating the cultured FDC with either TNF-alpha, IL-1 beta, IFN-gamma or granulocyte-macrophage-CSF; in contrast, IL-4 had no effect on CD54 but rather up-regulated expression of VCAM-1. IFN-gamma, unlike the other cytokines tested, increased expression of a set of markers on cultured FDC (CD54, VCAM-1, and CD14) and converted these class II-negative cells into class II+ cells. The fact that various T cell-derived cytokines have different effects on FDC suggests that the T cell products may influence the manner by which FDC stimulate B cell proliferation and maturation.
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PMID:Cultured human follicular dendritic cells. Growth characteristics and interactions with B lymphocytes. 137 41

Past studies have shown that contact between tumor cells and fibroblasts results in stimulation of collagenase production by the fibroblasts. Membrane fractions prepared by differential centrifugation of sonicated B-16 melanoma cells were shown here to contain a collagenase stimulatory factor(s) (CSF). Trypsin treatment of intact B-16 cells prior to membrane fractionation led to loss of 90% of the total activity, indicating that CSF is localized on the outer surface of the cells. Stimulation of fibroblast collagenase production was also observed with dialyzed octylglucoside extracts of the B-16 membranes. Additional of exogenous lipid, ie, a mixture of phosphatidylcholine and phosphatidylserine, to the detergent extract of the membranes followed by dialysis and centrifugation at 100,000g resulted in 80% recovery of the factor activity in the pellet containing reconstituted lipid vesicles. Fractionation of tritium-labeled, reconstituted lipid vesicles on a Sephacryl S-300 column revealed that the collagenase stimulatory factor coeluted with the radioactive lipid vesicles. The fractionated lipid vesicles lost stimulatory activity completely after trypsin treatment or heating at 65 degrees C, indicating that the factor is a protein.
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PMID:Membrane association of collagenase stimulatory factor(s) from B-16 melanoma cells. 282 6

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

It was investigated (1) whether metalloproteinase-9 (MMP-9), MMP-3, and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1, the natural tissue inhibitor of MMP-9) are increased in the CSF of patients with Lyme neuroborreliosis and (2) whether macrophages can express MMP-9 when stimulated with Borrelia burgdorferi. Zymography showed MMP-9 activity in 26 of 31 (84%) CSF samples from patients with acute stage 2 Lyme neuroborreliosis, but not in 20 controls with non-inflammatory neurological disorders. Activity of MMP-2 was detected in all CSF samples in both patients with neuroborreliosis and controls, suggesting a constitutive release of MMP-2. Using enzyme linked immunosorbent assay (ELISA) MMP-3 (which can activate MMP-9) was detected in low concentrations in the CSF of 13 of 29 patients with neuroborreliosis, but not in controls. TIMP-1 was increased twofold in CSF samples from patients with neuroborreliosis in comparison with the controls. MMP-9 activity was induced in vitro in a mouse macrophage cell line (RAW 264.7) when stimulated with two different genospecies of B burgdorferi (B garinii, B afzelii ). This MMP-9 activity was reduced in a dose dependent manner when macrophages stimulated with B burgdorferi were coincubated with NF-kappaB SN50, a cell permeable peptide which inhibits the translocation of NF-kappaB into the nucleus of stimulated cells. The data show that (1) MMP-9 activity is present in the CSF of patients with neuroborreliosis, (2) macrophages stimulated with B burgdorferi are a possible source of MMP-9 increase, and (3) activation of NF-kappaB may play a part in the upregulation of MMP-9 by B burgdorferi.
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PMID:Upregulation of matrix metalloproteinase-9 in the cerebrospinal fluid of patients with acute Lyme neuroborreliosis. 1067 23

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.
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PMID:Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis. 1152 76

The neuropathogenesis of HIV-1-associated dementia (HAD) revolves around the secretion of toxic molecules from infected and immune-competent mononuclear phagocytes. Astrocyte activation occurs in parallel but limited insights are available for its role in neurotoxicity and cognitive dysfunction. One means in which astrocytes may affect disease is through their production of tissue inhibitors of metalloproteinases (TIMPs). TIMPs are regulators of matrix metalloproteinases, enzymes that affect blood-brain barrier integrity through altering the extracellular matrix. We hypothesized that in response to injury and inflammation in HAD, astrocytes regulate the production of TIMP-1, the inducible type of TIMP that is important in inflammation. To address astrocyte-mediated TIMP-1 regulation in HAD, we evaluated the responses of primary human to IL-1beta and HIV-1. TIMP-1 levels in plasma, CSF, and brain tissue of control, HIV-1 infected patients without cognitive impairment, and HAD patients were also studied. Our data show that an upregulation of TIMP-1 results from astrocytes acutely activated with IL-1beta. In contrast, CSF and brain tissue samples from HAD patients showed reduced TIMP-1 levels compared to seronegative controls. MMP-2 levels in brains showed the opposite. Consistent with this, prolonged activation of astrocytes led to a reduction in TIMP-1 and MMP-2, but a sustained elevation in MMP-1. Our data suggest that in diseased brain tissue, the ability of astrocytes to counteract the destructive effects of MMP through expression of TIMP-1 is diminished by chronic activation. Our studies reveal new opportunities for repair-based therapeutic strategies in HAD.
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PMID:Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: links to HIV-1 dementia. 1295 56

Tumor necrosis factor-alpha (TNFalpha) and granulocyte macrophage colony-stimulating factor (GM-CSF) individually enhance monocyte matrix metalloproteinase-9 (MMP-9) but induce MMP-1 only when added in combination. Because interferon-gamma (IFNgamma) is also found at inflammatory sites, we determined its effect on monocyte MMPs in the presence or absence of TNFalpha and GM-CSF. IFNgamma alone did not stimulate monocyte MMP-9 or MMP-1; however, in the presence of GM-CSF it induced MMP-1 and enhanced MMP-1 stimulated by GM-CSF and TNFalpha. IFNgamma induced MMP-1 in the presence of GM-CSF through the stimulation of TNFalpha production through a mechanism involving both p38 and ERK1/2 MAPKs, in which GM-CSF stimulated ERK1/2 whereas IFNgamma activated p38. In support of this conclusion TNFalpha neutralizing antibody and antibodies against TNF receptor I and -II blocked the induction of MMP-1 by GM-CSF and IFNgamma. In contrast to its effects on MMP-1, IFNgamma inhibited TNFalpha-induced MMP-9 through a caspase 8-dependent pathway as demonstrated by the restoration of MMP-9 with caspase 8 inhibitors. Moreover, the phosphorylation of STAT1 by IFNgamma was blocked by an inhibitor of caspase 8, indicating that STAT1 had a suppressive effect on MMP-9. Caspase 8-mediated phosphorylation of STAT1 through p38 MAPK as shown by the inhibition of IFNgamma-induced phosphorylation of p38 by caspase 8 inhibitors. Activation of caspase 8 by IFNgamma did not result in increased apoptosis. Thus IFNgamma in the presence of GM-CSF and/or TNFalpha differentially regulates monocyte MMPs through induction of TNFalpha and a novel mechanism involving caspase 8 that is independent of apoptosis.
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PMID:Interferon-gamma differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis factor-alpha and caspase 8. 1296 Jan 56

Angiotensin II (Ang II)-mediated hypertension increases the risk for acute coronary syndrome, a consequence of atherosclerotic plaque rupture, which may be caused by matrix metalloproteinases (MMPs). Here, we show that human primary monocytes stimulated with tumor necrosis factor alpha (TNF-alpha) and granulocyte macrophage-colony stimulating factor (GM-CSF) release Ang II, which is an integral component of the signal transduction pathway that leads to MMP-1 production. An Ang II-mediated increase in MMP-1 synthesis occurred only in conjunction with cytokine stimulation. Moreover, Ang II mediated its effect through the Ang II type 2 (AT(2)) receptor, as demonstrated by enhancement of MMP-1 production by an AT(2) agonist, CGP-42112A, and inhibition of MMP-1 production by PD1233319, an AT(2) antagonist. Additionally, exogenous Ang II caused a significant enhancement in MMP-1 production by cytokine-stimulated monocytes, and the most effective enhancement occurrred when Ang II was added 6 h after stimulation. Furthermore, Ang II and the AT(2) agonist increased prostaglandin E(2) (PGE(2)), which in turn mediated the increase in MMP-1, as shown by the inhibition of MMP-1 by indomethacin or aspirin. In contrast, the AT(2) antagonist inhibited the PGE(2) production induced by TNF-alpha and GM-CSF. Ang II, through its interaction with the AT(2) receptor, has a central role in mediating the PGE(2)-dependent production of MMP-1 by monocytes stimulated with TNF-alpha and GM-CSF. These observations provide insight into the association between hypertension and acute coronary syndrome and a possible mechanism by which Ang-converting enzyme inhibitor and aspirin may reduce the risk for heart attacks.
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PMID:Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture. 1581 99


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