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)

The plasminogen activator (PA)/plasmin system has been implicated in the inflammation and connective tissue remodelling occurring in arthritic joints. PA activity is detected in cultures of human monocytes, synoviocytes and chondrocytes and can be regulated by a variety of cytokines found in diseased joints; PA inhibitors (PAI-1 and/or PAI-2) are also produced by these cells. We have shown that human monocytes can synthesize both urokinase-type PA (u-PA) and tissue-type PA (t-PA). One cytokine present in rheumatoid synovial fluids, granulocyte macrophage colony stimulating factor (GM-CSF), stimulates monocyte u-PA production; since this cytokine can also be produced by activated monocytes and other cell types in joints, than a "CSF network" can be produced leading to u-PA production. Another monocyte cytokine, interleukin 1, causes human synoviocytes to increase their u-PA expression, a response which can be dependent on the presence of endogenous cyclooxygenase products; this cytokine also causes human chondrocytes and cartilage tissue to produce increased u-PA and t-PA activity, i.e., under conditions during which cartilage is resorbed.
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PMID:Regulation of plasminogen activator activity in arthritic joints. 190 74

The v-fms oncogene of the McDonough strain of feline sarcoma virus (SM-FeSV) encodes a plasma-membrane-associated tyrosine kinase (gp140v-fms) which is closely related, both structurally and functionally, to the c-fms-specified receptor for the macrophage colony stimulating factor (CSF-1). In mammalian fibroblasts, the natural producers of CSF-1, expression of v-fms leads to cell transformation. To study the interaction between CSF-1 and gp140v-fms molecules in a cell system that does not produce endogenous cross-reactive CSF-1, we have expressed the entire v-fms gene as well as a nontransforming deletion mutant (SC2) in chicken embryo cells (CEC). For this purpose the avian retroviral vectors pDS3 and pREP, based on Rous sarcoma virus, were used to isolate recombinant virus particles. CEC infected with virus that carried the entire v-fms gene expressed high amounts of gp140v-fms, comparable to those in SM-FeSV transformed NRK cells. However, these CEC remained flat, retained their fibronectin network, and did not produce enhanced levels of plasminogen activator. The cells grew faster than control CEC for more than 8 weeks but failed to form colonies in soft agar. Within 2 days after addition of CSF-1 to the growth medium, a transformed cell phenotype was induced, as judged by loss of the fibronectin network, again with a growth rate fourfold faster than that of the parental cells and with colony formation in soft agar. Moreover, human CSF-1 caused a rapid tyrosine phosphorylation of v-fms molecules detectable within 5 min after addition of the growth factor. In contrast, CSF-1 had none of the above effects on cells that expressed the SC2 v-fms deletion mutant.
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PMID:Transformation of chicken fibroblasts by the v-fms oncogene. 217 Nov 88

Mouse resident peritoneal macrophages synthesize two plasminogen activator-specific inhibitors (PAI) that are functionally and antigenically related, but differ in their apparent Mr and oligosaccharide content. Most of the Mr 40,000 inhibitor can be recovered from the cell lysate, whereas the Mr 55,000 glycosylated PAI is preferentially secreted. The murine macrophage PAI are functionally similar and immunologically related to PAI synthesized and secreted by human monocytes-macrophages, and to a PAI from human placenta (PAI-2). PAI production by murine mononuclear phagocytes can be modulated both in vivo and in vitro. Bone marrow-derived macrophages do not produce detectable PAI, whereas inflammatory macrophages obtained from thioglycollate-induced peritoneal exudates produce only low levels of PAI. In cultures of resident peritoneal macrophages, phorbol myristate acetate and cholera toxin increase the synthesis of the Mr 55,000 secreted PAI, whereas dexamethasone decreases the synthesis of both PAI; the production of PAI is also enhanced in the presence of macrophage colony-stimulating factor (CSF-1). The overall proteolytic activity of mononuclear phagocytes thus depends in part on the controlled synthesis and secretion of PAI. The balance between the production of plasminogen activators and of their inhibitors could be critical in determining the level of plasminogen-dependent extracellular proteolysis associated with different phases of the inflammatory response.
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PMID:Plasminogen activator-specific inhibitors in mouse macrophages: in vivo and in vitro modulation of their synthesis and secretion. 311 28

CSF-1 is a hemopoietic growth factor that specifically causes the proliferation and differentiation of mononuclear phagocytic cells. J774 cells are a monocyte precursor-like macrophage cell line. This transformed macrophage cell line exhibits specific 125I-CSF-I-binding activity similar to that of normal murine macrophages, although its survival and growth is independent of CSF-1. At 0 degrees C, saturation of binding sites was achieved at 240 pM 125I-CSF-1. At 37 degrees C, the bound 125I-CSF-1 was rapidly internalized and degraded by the target cells with a T1/2 of approximately 30 min; degradation was inhibited by the addition of NH4Cl. The addition of CSF-1 to cultures caused dose-dependent inhibition rather than stimulation of [3H]thymidine uptake by J774 cells. Whereas CSF-1 stimulated the clonal growth of normal mouse peritoneal exudate macrophages, it inhibited the clonal growth of J774 cells in agar cultures. Furthermore, CSF-1 exhibited a concentration-dependent enhancement of the production of plasminogen activator (PA) by J774 cells. The enhanced production of PA was detected 6 hr after the addition of CSF-1 and was inhibited by the simultaneous addition of the anti-inflammatory drug. It appears that the effects of CSF-1 on cell proliferation and PA production by CSF-1 receptor-bearing cells are mediated by distinct intracellular pathways albeit through the same receptor.
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PMID:Colony-stimulating factor (CSF-1): its enhancement of plasminogen activator production and inhibition of cell growth in a mouse macrophage cell line. 632 11

The tumor-promoting phorbol ester, 12-0-tetradecanoyl-phorbol-13-acetate (TPA), stimulates starch-elicited mouse peritoneal macrophages to undergo DNA synthesis in vitro, apparently without the generation of an endogenous macrophage growth factor (MGF). No evidence was found for any synergistic interaction between TPA and exogenous colony stimulating factors (CSFs) for macrophage DNA synthesis. Low concentrations of glucocorticoids and also prostaglandins E1 and E2 suppress both the CSF-1-stimulated and the TPA-stimulated macrophage DNA synthesis; these same drugs inhibit the CSF-1-mediated and TPA-mediated enhancement of macrophage plasminogen activator (PA) activity. Thus glucocorticoids and prostaglandins E1 and E2 oppose the action of growth factors and the tumor promoter on macrophage and precursor cell function.
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PMID:Glucocorticoids and prostaglandins inhibit the induction of macrophage DNA synthesis by macrophage growth factor and phorbol ester. 660 Nov 10

Various growth factors released by macrophages and other cell types modulate normal hematopoiesis. The physiological mechanisms whereby these molecules interact with specific target cells are ill defined. Eicosanoids, the products of fatty acid metabolism, are known to regulate cell proliferation and differentiation. The release of membrane-bound phospholipid by phospholipase-A2 (PLA-2) is the first critical step in the initiation of membrane remodeling and eventually eicosanoid synthesis. We report here data that demonstrates how various cytokines exhibit a marked hydrolytic activity mediated through PLA-2 against both [1-14C] oleic acid- and [1-14C] arachidonic acid-labeled Escherichia coli (micelle) substrates. PLA-2 extracts were prepared from neutrophils elicited by injecting rats ip with 8% glycogen. The rate of hydrolysis of free fatty acids from the phospholipid substrate was found to be linear, rapid, and pH dependent and was calculated to be 30 nmoles of phospholipid/hr/mg protein lysate. Cytokines (i.e., interleukin-1 [IL-1, human and murine recombinant, alpha], mouse lung cell-derived colony-stimulating factor [L-CSF], granulocyte-macrophage colony-stimulating factor [murine recombinant GM-CSF], tumor necrosis factor [murine recombinant TNF-alpha], and granulocyte colony-stimulating factor [human recombinant, G-CSF] all induced PLA-2 activity with the release of free fatty acids above basal levels. In contrast, lipopolysaccharide (LPS), interleukin-2, (IL-2, human recombinant), and macrophage colony-stimulating factor (M-CSF) did not significantly activate PLA-2 hydrolysis. The activation of this membrane-bound enzyme-substrate complex by these growth factors may serve as a mechanism whereby the appropriate target cells expressing receptors respond through either direct or secondary signals leading to the formation of free fatty acids with the eventual synthesis of prostanoid or lipoxygenase products, resulting in cellular proliferation and differentiation.
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PMID:The regulation of phospholipase-A2 (PLA-2) by cytokines expressing hematopoietic growth-stimulating properties. 865 Feb 56

Human ovarian adenocarcinoma cells N.1 secrete an autocrine activity that stimulates active cell death under serum-reduced conditions. To substitute the autocrine activity by a single physiological component, 28 cytokines, growth factors and biomodulators were tested [interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, stem cell factor (SCF), platelet-derived growth factor (PDGF), acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), IGF-2, insulin, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin, RANTES (regulated on activation normal T cell expressed and secreted), angiogenin, leukaemia inhibitory factor (LIF), erythropoietin (EPO), interferon alpha (INF-alpha), INF-gamma, transferrin, tumour necrosis factor alpha (TNF-alpha, TNF-beta and bovine serum albumin for control reasons]. In these experiments, only TNF-alpha and TNF-beta rapidly induced apoptosis. TNF-alpha and TNF-receptor 1 were expressed by N.1 cells, and the secretion of TNF-alpha was verified by enzyme-linked immunosorbent assay (ELISA). Autocrine factor-triggered apoptosis was inhibited when conditioned supernatant was preincubated with anti-TNF-alpha antibody. These findings suggested that the apoptosis-inducing component of the N.1 autocrine activity was TNF-alpha. In the presence of antisense c-myc oligonucleotides, induction of cell death by autocrine factor was partly inhibited. Autocrine factor and TNF-alpha stimulated transcription of the invasiveness-related protease plasminogen activator/urokinase mRNA (upa) with similar kinetics. When N.1 cells were exposed to purified plasminogen activator/urokinase protein (uPA), cell matrix contact was disrupted. Thus, uPA might serve a physiological role during TNF-induced apoptosis by affecting the interactions between cells and the basal membrane, thereby facilitating anoikis. This mechanistic study, which was restricted to a single human ovarian carcinoma model cell line (N.1), provides evidence that N.1 maintains the capacity to undergo c-myc-dependent apoptosis by the TNF-TNF-receptor pathway, and no additional pharmacological stimuli for induction of apoptosis are required.
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PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

Inflammatory process plays an important role in the development and progression of atherosclerotic lesions. Recently, group-II phospholipase A(2) (PLA(2)), an inflammatory mediator, was reported to exist in human atherosclerotic lesions and to enhance the development of murine atherosclerotic lesions. Oxidized low density lipoprotein (Ox-LDL) stimulates the growth of several types of macrophages in vitro. Since proliferation of macrophages occurs in atherosclerotic lesions, it is possible to assume that the Ox-LDL-induced macrophage proliferation might be involved in the progression of atherosclerosis. In this study, the role of group-II PLA(2) in the Ox-LDL-induced macrophage growth was investigated using thioglycollate-elicited mouse peritoneal macrophages. Thioglycollate-elicited macrophages significantly expressed group-II PLA(2) and released it into the culture medium. The Ox-LDL-induced thymidine incorporation into thioglycollate-elicited macrophages was three times higher than that into resident macrophages, whereas under the same conditions, granulocyte/macrophage colony-stimulating factor (GM-CSF) equally induced thymidine incorporation into both types of macrophages. Moreover, the Ox-LDL-induced GM-CSF release from thioglycollate-elicited macrophages was significantly higher than that from resident macrophages. In addition, the Ox-LDL-induced thymidine incorporation into macrophages obtained from human group-II PLA(2) transgenic mice and the GM-CSF release from these cells were significantly higher than those from their negative littermates, and the Ox-LDL-induced thymidine incorporation into human group-II PLA(2) transgenic macrophages was significantly inhibited by a polyclonal anti-human group-II PLA(2) antibody. These results suggest that the expression of group-II PLA(2) in thioglycollate-elicited macrophages may play an enhancing role in the Ox-LDL-induced macrophage growth through the enhancement of the GM-CSF release.
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PMID:Group-II phospholipase A(2) enhances oxidized low density lipoprotein-induced macrophage growth through enhancement of GM-CSF release. 1105 98

High level of phospholipase A(2) (PLA(2)) activity is found in serum and biological fluids during the acute-phase response (APR). Extracellular PLA(2) in fluids of patients with inflammatory diseases such as sepsis, acute pancreatitis or rheumatoid arthritis is also associated with propagation of inflammation. PLA(2) activity is involved in the release of both pro- and anti-inflammatory lipid mediators from phospholipids of cellular membranes or circulating lipoproteins. PLA(2) may thus generate signals that influence immune responses. Here, group III secretory PLA(2) were tested for their ability to promote generation of functionally mature human dendritic cells (DC). PLA(2) treatment of differentiating monocytes in the presence of granulocyte/macrophage colony-stimulating factor and IL-4 yielded cells with phenotypical and functional characteristics of mature DC. This maturation was dependent on the dose of PLA(2), and PLA(2)-generated DC stimulated IFN-gamma secretion by allogeneic T cells. The effects of PLA(2) on DC maturation was mainly dependent on enzyme activity and correlated with the activation of NF-kappaB, AP-1 and NFAT. The data suggest that transient increase in PLA(2) activity generates signals that promote transition of innate to adaptive immunity during the APR.
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PMID:Secretory phospholipase A2 induces dendritic cell maturation. 1525 27

Tobacco smoking is an important risk factor for the development of severe periodontitis. Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1 (PAI-1), alpha7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1 proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3, and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the alpha7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13, thereby tipping the balance between bone matrix formation and resorption toward the latter process.
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PMID:Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. 1715 81


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