Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Invasion of tissue by monocytes in the course of cellular immune reactions is a multistep process that is thought to be based on the action of urokinase type plasminogen activator (u-PA), an ubiquitous serine protease able to convert the zymogen plasminogen into the active protease plasmin. Expression and occupation of urokinase-type plasminogen activator receptors (u-PA-R) are known to be up-regulated by IFN-gamma and TNF-alpha, and endogenously occupied u-PA-R were found to be instrumental in monocyte invasiveness. We used the amnion invasion assay to investigate whether monocyte invasiveness is affected by matrix-bound plasminogen activator inhibitors (PAI) and by fluid phase u-PA. We show in this study that preincubation of amnion membranes with 1.5 U/cm2 PAI-1 decreases invasion of IFN-gamma activated monocytes by 70% compared with controls. Anti-vitronectin antibodies, which block PAI-1 binding to the matrix, abrogate the inhibitory effect of PAI-1 on monocyte invasiveness, indicating that active PAI-1 is bound via matrix-associated vitronectin. In contrast, preincubation of the amnion membrane with PAI-2 which does not bind to the extracellular matrix has no effect on monocyte invasiveness. Finally, the inhibitory action of matrix-bound PAI-1 can be abrogated by addition of 5 IU/ml u-PA to the monocytes in the invasion chamber. These findings indicate that monocyte invasiveness might be regulated not only by expression and occupation of u-PA-R but also by matrix-bound PAI-1.
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PMID:Matrix-bound plasminogen activator inhibitor type 1 inhibits the invasion of human monocytes into interstitial tissue. 169

Plasmin reacted readily with recombinant murine interferon-gamma (rIFN-gamma) in vitro, reducing the relative molecular mass of each monomer by approximately 1,000. The amino terminus of the rIFN-gamma remained intact and no sites of internal peptide bond hydrolysis were detected, indicating that the plasmin target region is most likely near the carboxyl terminus. Cleavage of rIFN-gamma was observed with similar concentrations of trypsin or min-plasmin. By contrast, human neutrophil elastase failed to alter the structure of rIFN-gamma. The plasma proteinase inhibitor, alpha 2-antiplasmin, protected rIFN-gamma from plasmin digestion. Purified alpha 2-macroglobulin-plasmin complex cleaved rIFN-gamma; however, the activity was greatly reduced compared with the free proteinase. The antiviral activity of the rIFN-gamma was enhanced four- to fivefold by treatment with plasmin or trypsin. By contrast, naturally occurring murine IFN-gamma was inactivated by plasmin (80%), suggesting that the effect of plasmin on IFN activity can vary depending on the preparation studied. The importance of plasmin at the site of an immune reaction is well established. This investigation identifies plasmin and miniplasmin as physiologic proteinases capable of reacting with IFN-gamma in vivo.
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PMID:Cleavage of recombinant murine interferon-gamma by plasmin and miniplasmin. 252 20

Macrophages have a marked capacity to invade tissue in the course of cellular immune reactions that is thought to be based on the action of urokinase (u-PA). u-PA is an ubiquitous serine protease that converts the zymogen plasminogen into the active protease plasmin. u-PA binds to specific receptors on the macrophage thereby enabling the cell to degrade interstitial tissue in the microenvironment. Two cytokines produced in the course of cellular immune reactions, IFN-gamma and TNF-alpha, increase the number of u-PA receptors on human cultured monocytes from 14,000 to 64,000 and 30,000 receptors/cell, respectively. We used an amnion invasion assay to investigate whether activated human monocytes exhibit an enhanced capacity to invade interstitial tissue in correlation to the increased numbers of u-PA receptors. We show in this study that IFN-gamma, which increases the number of endogenously occupied and saturable u-PA receptors, causes a threefold increase of monocyte invasion into amnion tissue in comparison to control cells. The anti-u-PA mAb MPW5UK, which blocks the activity of u-PA, inhibits monocyte invasiveness significantly. In contrast, TNF-alpha, which increases only the number of saturable u-PA receptors on monocytes, does not enhance their invasiveness. This finding suggests that only endogenously occupied u-PA receptors are instrumental in monocyte invasiveness. This conclusion is further supported by the findings that: 1) saturation of monocytes with u-PA does not further increase their invasiveness and that 2) plasminogen-activator inhibitor-2, a specific inhibitor of u-PA associated with endogenously occupied, but not of u-PA bound to saturable receptors, inhibits monocyte invasiveness completely.
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PMID:Endogenous receptor-bound urokinase mediates tissue invasion of human monocytes. 255 65

Mononuclear phagocytes produce proteinases that are thought to play a role in regulating the activity of cytokines. Activated macrophages secrete urokinase-type plasminogen activator (uPA), which mediates the formation of the serine proteinase plasmin from the ubiquitous zymogen plasminogen. We previously observed a correlation between in vitro plasminogen activation by the promonocytic cell line U937 and the apparent ability of these cells to inactivate recombinant interferon-gamma (rIFN-gamma) by proteolysis. The present study was designed to test the hypothesis that plasmin, generated in U937 cell cultures, is both necessary and sufficient to inactivate rIFN-gamma by limited proteolysis. The following observations are consistent with this hypothesis: (1) inactivation of rIFN-gamma was prevented by inhibitors of serine proteinases or an antibody that specifically immunodepleted plasmin activity; (2) purified plasmin inactivated rIFN-gamma as efficiently as U937 culture supernatants and was similarly sensitive to serine proteinase inhibitors; and (3) plasmin removed an 11 amino acid carboxyl-terminal peptide from rIFN-gamma, which included a region known to be required for bioactivity. Overall, these data indicate that plasminogen activation by U937 promonocytic cells leads to the proteolytic inactivation of IFN-gamma by a process that only requires the production of plasmin.
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PMID:Mechanism by which U937 promonocytic cells inactivate human interferon-gamma. 755 25

The plasmin/plasminogen system of enzymes may be involved in leukocyte migration through the endothelial cell layer of the vascular wall during inflammatory processes associated with vascular injury, atherosclerosis, and sepsis. Synthesis of plasminogen activator inhibitor type 1 (PAI-1) by the endothelium may protect these cells and the subendothelial cell matrix from excessive degradation and retard leukocyte migration. We report in this work for the first time the down-regulation of both basal and thrombin- or endotoxin-induced PAI-1 in cultured human endothelial cells by the activated T cell product, IFN-gamma. Down-regulation of basal and thrombin- or endotoxin-induced endothelial PAI-1 protein by IFN-gamma was found to be both time and dose dependent. Decreases of up to 71% relative to thrombin- or endotoxin-treated controls, using an optimal IFN-gamma concentration of between 20 and 200 U/ml, were found for human macrovascular and microvascular endothelial cells. However, IFN-gamma did not appear to affect IL-1 alpha- and TNF-alpha-induced levels of PAI-1 protein or mRNA in these cells. Northern blot analysis paralleled protein results, showing decreases in specific endothelial cell thrombin- or LPS-induced PAI-1 mRNA expression, respectively, after incubation with IFN-gamma for 24 h. These results suggest a means by which the migration of circulating leukocytes through endothelial cell layers during inflammation may be facilitated.
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PMID:IFN-gamma inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells. 880 64

Inflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma are increased in sera and lesions of Kaposi's sarcoma (KS) patients. Previous data have indicated that the combination of these cytokines as found in conditioned media from activated T cells induces normal endothelial cells to acquire the features of KS spindle cells (KS cells) including spindle morphology, marker expression, and the responsiveness to the effects of HIV-1 Tat protein. Conditioned media from activated T cells or the single cytokines also induce AIDS-KS cells to produce and release basic fibroblast growth factor (bFGF). bFGF is highly expressed also by in situ KS cells and mediates KS-like lesion formation after inoculation of the cells in nude mice. Here we show that both large and small vessel endothelial cells chronically exposed to inflammatory cytokines produce and release bioactive bFGF in the absence of cell death. In addition, after this treatment, endothelial cells acquire angiogenic capability and induce KS-like lesions after inoculation in nude mice. Production and release of bFGF is induced in a synergistic fashion by TNF-alpha, IL-1beta, and IFN-gamma, and its release is further promoted by low cell density and by the serine proteases plasmin and thrombin. These results indicate that inflammatory cytokines induce endothelial cells to export bFGF and to acquire angiogenic properties, a key feature of the KS cell phenotype, and suggest a mechanism by which these cytokines can cooperate in the induction of KS.
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PMID:Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice. 902 30

Ceruloplasmin is a 132-kDa glycoprotein abundant in human plasma. It has multiple in vitro activities, including copper transport, lipid pro- and antioxidant activity, and oxidation of ferrous ion and aromatic amines; however, its physiologic role is uncertain. Although ceruloplasmin is synthesized primarily by the liver in adult humans, production by cells of monocytic origin has been reported. We here show that IFN-gamma is a potent inducer of ceruloplasmin synthesis by monocytic cells. Activation of human monoblastic leukemia U937 cells with IFN-gamma increased the production of ceruloplasmin by at least 20-fold. The identity of the protein was confirmed by plasmin fingerprinting. IFN-gamma also increased ceruloplasmin mRNA. Induction followed a 2- to 4-h lag and was partially blocked by cycloheximide, indicating a requirement for newly synthesized factors. Ceruloplasmin induction in monocytic cells was agonist specific, as IL-1, IL-4, IL-6, IFN-alpha, IFN-beta, TNF-alpha, and LPS were completely ineffective. The induction was also cell type specific, as IFN-gamma did not induce ceruloplasmin synthesis in endothelial or smooth muscle cells. In contrast, IFN-gamma was stimulatory in other monocytic cells, including THP-1 cells and human peripheral blood monocytes, and also in HepG2 cells. Ceruloplasmin secreted by IFN-gamma-stimulated U937 cells had ferroxidase activity and was, in fact, the only secreted protein with this activity. Monocytic cell-derived ceruloplasmin may contribute to defense responses via its ferroxidase activity, which may drive iron homeostasis in a direction unfavorable to invasive organisms.
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PMID:Induction of ceruloplasmin synthesis by IFN-gamma in human monocytic cells. 925 59

In addition to the known function in the glycolytic pathway, phosphoglycerate kinase 1 (PGK-1) promotes reduction of plasmin disulfide bonds leading to angiostatin formation and inhibition of tumor angiogenesis. In this study, the effects of PGK-1 on anti- tumor immunity against lung cancer were evaluated using the Tet-Off control of PGK-1 expression in the Lewis lung carcinoma (LLC-1). There was no significant difference in cell proliferation between parental LLC-1 and LLC-1 transduced with PGK-1 (PGK-LLC-1). However, expression of PGK-1 was found to limit tumor growth in mice subcutaneously injected with the cell lines and tumor growth was restored after doxycycline treatment. In addition, the cell invasion ability of PGK-LLC-1 became weaker than that of LLC-1. Expressions of COX-2, TGF-beta1 and PGE2 were all found to be down-regulated in PGK-LLC-1. PGK-LLC-1 cells treated with doxycycline recovered their COX-2 protein expression. In the presence of conditioned medium from PGK-LLC-1, the endothelial cell migration was reduced. Moreover, PGK-LLC-1 also stimulated T lymphocytes to express higher levels of Th1 cytokine (IFN-gamma) and lower levels of IL-10 in comparison with parental LLC-1. PGK-LLC-1 cells restored the growth rate in immunodeficient mice when compared with the growth rate in normal mice. In the tissue sections, reduced COX-2 expressions and marked infiltrated CD3 T lymphocytes were observed in the PGK-LLC-1 injected group. These findings indicate that overexpression of PGK-1 in LLC-1 reduces the COX-2 expression, and, in turn, affect PGE2, cell invasion, angiogenesis, and the immune functions, and finally inhibit the tumor progression.
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PMID:Phosphoglycerate kinase 1-overexpressing lung cancer cells reduce cyclooxygenase 2 expression and promote anti-tumor immunity in vivo. 1881 80