Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 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

Macrophage products induce production of proteases that contribute to cartilage degradation in various joint diseases. In these studies we stimulated rabbit chondrocytes with various cytokines in vitro in order to determine which were responsible for changes in the release of prostaglandin, plasminogen activator, and a metalloproteinase. The metalloproteinase assayed in these studies is a latent enzyme whose activity can rapidly be measured with fluorogenic casein. Conditioned media from stimulated human peripheral blood mononuclear cells; purified human monocyte IL 1, pI 7,6, and 5; and recombinant human IL 1, beta or alpha forms, all changed the secretory pattern of rabbit articular chondrocytes in a similar manner: production and secretion of a latent metalloproteinase(s) and prostaglandin E were stimulated in a concentration-dependent fashion, whereas the activity of plasminogen activator was strongly reduced. Antibodies against human monocyte IL 1 blocked the active principle in various mononuclear cell-conditioned media, suggesting that uncharacterized factors present in these supernatants do not affect the metalloproteinase response. When added to confluent chondrocytes, phorbol myristate acetate, concanavalin A, IL 2, lipopolysaccharide, indomethacin, and prostaglandin E2, which interfere with lymphocyte proliferation assays for IL 1, failed to influence chondrocyte metalloproteinase secretion. Recombinant human IFN-alpha or IFN-gamma in the presence or absence of IL 1 had no effect on rabbit chondrocytes, whereas recombinant human tumor necrosis factor decreased plasminogen activator but had no effect on prostaglandin or metalloproteinase production. These results support the concept that IL 1 specifically induces chondrocytes to produce metalloproteinases, and hence may play an important role in destructive joint diseases.
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PMID:Human monocyte or recombinant interleukin 1's are specific for the secretion of a metalloproteinase from chondrocytes. 309 47

A cell culture model has been established employing normal human articular or costal chondrocytes in monolayer culture as target cells for the effects of intercellular mediators on chondrocyte function, particularly collagen synthesis. Recombinant Interleukin-1 (IL-1) which stimulates the synthesis of prostaglandin E2 (PGE2), collagenase, and plasminogen activator also stimulates the synthesis of collagen and increases steady-state levels of mRNA in cultured chondrocytes, synovial cells and foreskin fibroblasts if the synthesis of PGE2, which inhibits collagen synthesis, is inhibited by indomethacin. Recombinant immune interferon (IFN-gamma), which does not affect collagenase of PGE2 production, suppresses type II as well as types I and III collagen synthesis and associated mRNA levels. IL-1 and IFN-gamma could therefore have opposite roles in modulating cartilage matrix turnover in joint disease by affecting repair as well as degradation.
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PMID:Control of collagen synthesis in human chondrocyte cultures by immune interferon and interleukin-1. 311 88

Monocyte or macrophage polykaryons (MP) are seen in different tissues in various inflammatory states and in normal bone (osteoclasts). The factors controlling the formation and the function of MP are not completely understood. This study was designed to evaluate the effects of the lymphokine gamma-interferon (IFN-gamma) on human monocyte function in vitro. Purified recombinant IFN-gamma [20-200 units/ml (0.1-1.0 nM)] caused the appearance of MP in cultures of normal human monocytes cultured in 10% unheated autologous serum. The MP were noted by as early as 36 hr of culture with fusion indices of 40%-60% and up to 160 nuclei per cell. The effect was seen with both recombinant IFN-gamma and natural IFN-gamma produced by Staphylococcal enterotoxin A-stimulated lymphocytes, but IFN-alpha (leukocyte-derived and recombinant) and IFN-beta did not induce MP formation. The activity of the IFN-gamma was destroyed by heating at 56 degrees C for 4 hr, incubating at pH 2 for 3 hr, or incubating with antibody against IFN-gamma. Populations of monocytes incubated 3 days with 100 units of IFN-gamma per ml (0.5 nM) had enhanced capacity to produce H2O2 in response to phorbol 12-myristate 13-acetate and increased content of acid phosphatase and plasminogen activator. As determined by autoradiography, the MP did not incorporate [3H]dThd into their nuclei. Thus, the IFN-gamma appears to induce MP formation by a process of monocyte fusion, and to "activate" monocytes, as judged by various parameters.
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PMID:Recombinant human gamma-interferon induces human monocyte polykaryon formation. 643 9

We investigated the effect of interferon-alpha 2 (IFN-alpha 2) on interleukin-1 alpha (IL-1 alpha)-induced up-regulation of urokinase type plasminogen activator (u-PA) expression in human foreskin microvascular endothelial cells (HFMEC) and human umbilical vein endothelial cells (HUVEC) in vitro. When IFN-alpha 2 and IL-1 alpha were added to the cells simultaneously, IFN-alpha 2 inhibited IL-1 alpha-induced up-regulation of u-PA antigen in a dose- and time-dependent fashion in HFMEC, whereas in HUVEC no effect of IFN-alpha 2 on IL-1 alpha-induced u-PA was seen. IL-1 alpha-induced up-regulation of PAI-1 antigen in HFMEC was not counteracted by IFN-alpha 2. When IFN-alpha 2 was added to HFMEC 1 or 2 h after IL-1 alpha a significant inhibition in u-PA synthesis was seen, whereas when IFN-alpha 2 was added to the cells 8 h after IL-1 alpha no effect on the induction of u-PA synthesis by IL-1 alpha was seen. IFN-alpha 2 also inhibited significantly the IL-1 alpha stimulated up-regulation of specific u-PA mRNA expression. In conclusion, our data show that IFN-alpha 2 can counteract the IL-1 alpha-induced up-regulation of u-PA in a similar way as IFN-gamma. This effect, which seems to be specific for microvascular endothelial cells, could contribute to the modulation of endothelial cell-mediated extravascular proteolysis in processes such as wound healing, neovascularisation, and endothelial cell migration.
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PMID:Interferon-alpha 2 counteracts interleukin-1 alpha-stimulated expression of urokinase-type plasminogen activator in human foreskin microvascular endothelial cells in vitro. 806 Nov 14

The effect of interferons IFN-alpha and IFN-gamma on the production of plasminogen activators (PAs) and plasminogen activator inhibitors (PAIs) was examined in human retinal pigment epithelial (RPE) cells in culture. Cultures of human RPE cells were incubated with either of the interferons for 48-96 h. The cell cultures were assayed using mRNA analysis and solid-phase immunocapture assay. Both interferons caused a marked decrease in PAI-1 mRNA expression after 48 h with no change in urokinase-type plasminogen activator (u-PA) mRNA expression. A marked decrease in PAI-1 activity and concomitant increase in u-PA activity in the culture medium appeared only after 72-96 h. We conclude that IFN-alpha and IFN-gamma stimulate plasminogen-mediated pericellular proteolysis of human RPE cells in culture by inhibiting PAI-1 gene expression.
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PMID:Alpha- and gamma-interferon inhibit plasminogen activator inhibitor-1 gene expression in human retinal pigment epithelial cells. 813 84

The susceptibility of native recombinant interferon gamma (rIFN-gamma, Actimmune) and recombinant tissue-type plasminogen activator (rt-PA, Activase) to methionine oxidation when treated with the oxidizing agent t-butyl hydroperoxide (TBHP) was investigated. The results showed that two of the five methionine residues in rIFN-gamma were susceptible to oxidation by TBHP, while three of the five methionines in rt-PA were found to be oxidizable. The oxidized methionine residues were found to be in the sulfoxide [Met(O)] form, and no other residue(s) appeared to be modified during the TBHP treatment. These results also showed that during treatment of a native protein with TBHP only the exposed methionine residues were oxidized. The biological activity of both molecules were unaffected by the treatment with TBHP. A comparative study between TBHP and hydrogen peroxide (H2O2) demonstrated that H2O2 was also a methionine-specific oxidizer. However, this study also showed that H2O2 was not able to distinguish between exposed and buried methionine residues, as significant portions of all five methionine residues in native rIFN-gamma were oxidized by treatment with H2O2. TBHP should be useful for identifying surface methionine residues in a protein of unknown structure and a valuable reagent for methionine oxidation in pharmaceutical stability studies.
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PMID:The use of t-butyl hydroperoxide as a probe for methionine oxidation in proteins. 861 96

Interleukin (IL-)1 stimulates prostaglandin E(2)(PGE(2)) generation in fibroblasts, and preferential couplings between particular phospholipase A(2)(PLA(2)) and cyclooxygenase (COX) isozymes are implicated with IL-1-induced delayed PGE(2)generation. The regulatory effects of interferon (IFN)-gamma and IL-4 on IL-1beta-induced COX, PLA(2)isoforms expression and terminal delayed PGE(2)generation were examined in three types of human fibroblasts. These human fibroblasts constitutively expressed cytosolic PLA(2)(cPLA(2)) and COX-1 enzymes, and exhibited delayed PGE(2)generation in response to IL-1beta. IL-1beta also stimulated expression of cPLA(2)and COX-2 only, while constitutive and IL-1beta-induced type IIA and type V secretory PLA(2)s (sPLA(2)s) expression could not be detected. A COX-2 inhibitor and cPLA(2)inhibitor markedly suppressed the IL-1beta-induced delayed PGE(2)generation, while a type IIA sPLA(2)inhibitor failed to affect it. IFN-gamma and IL-4 dramatically inhibited the IL-1beta-induced delayed PGE(2)generation; these cytokines apparently suppressed IL-1beta-stimulated COX-2 expression and only weakly suppressed cPLA(2)expression in response to IL-1beta. These results indicate that IL-1beta-induced delayed PGE(2)generation in these human fibroblasts mainly depends on de novo induction of COX-2 and cPLA(2), irrespective of the constitutive presence of COX-1, and that IFN-gamma and IL-4 inhibit IL-1beta-induced delayed PGE(2)generation by suppressing, predominantly, COX-2 expression.
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PMID:Interferon-gamma and interleukin 4 inhibit interleukin 1beta-induced delayed prostaglandin E(2)generation through suppression of cyclooxygenase-2 expression in human fibroblasts. 1084 35

Phospholipase A(2) (PLA(2)) is one of the major honey bee venom allergens for humans. To assess the long-term prevention of allergic reactions by DNA vaccination, a PLA(2)-CBA/J mouse model was employed using empty or PLA(2) sequence-carrying DNA plasmids. Early skin application of either DNA construct before (prophylactic approach) or after (therapeutic approach) sensitization with PLA(2)/alum led to reduced PLA(2)-specific IgE and IgG1 titers at 7 mo, with concomitant rise in IgG2a and IgG3. Splenocytes recovered at 5-6 mo after the last DNA administration exhibited a sustained IFN-gamma and IL-10 secretion and reduced IL-4 production. Recall challenge with PLA(2) boosted IFN-gamma and IL-10 secretion, suggesting the reactivation of quiescent memory Th1 lymphocytes. Mice from the prophylactic groups were fully protected against anaphylaxis, whereas 65% of the animals recovered in the therapeutic groups. Th1-polarized immune responses were also active in mice vaccinated with an empty plasmid 32 wk before sensitization with another Ag (OVA). This is the first demonstration that the Ag-coding sequence in DNA vaccine is not necessary to promote immune modulation in naive and sensitized animals for a prolonged period, and has relevance for the understanding of the innate and induced mechanisms underlying gene immunotherapy in long-term treatment of allergy.
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PMID:Antigen-independent suppression of the allergic immune response to bee venom phospholipase A(2) by DNA vaccination in CBA/J mice. 1120 23

Cytokines and growth factors that influence both secretion of the extracellular matrix (ECM) proteins and migration of the cells decide about the final outcome of tissue remodelling. We have examined expression of the components of the plasminogen activation system in human astrocytoma U373-MG cells and found that interleukin 1beta (IL-1beta), tumour necrosis factor alpha TNF-alpha), interferon gamma (INF-gamma) and epidermal growth factor (EGF) specifically regulate the expression of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor type 1 (PAI-1) and protease nexin-1 (PN-1). We conclude that EGF and IFN-gamma are new important regulators of the plasminogen activation system in astrocytoma cells and, therefore, may influence turnover of extracellular matrix and migration of cells within the brain.
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PMID:Epidermal growth factor and pro-inflammatory cytokines regulate the expression of components of plasminogen activation system in U373-MG astrocytoma cells. 1181 14


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