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 effects of glucocorticoids on biochemical functions of macrophages from man, mouse, rabbit, and guinea pig were examined. Secretion of plasminogen activator by human peripheral blood monocytes was decreased by 50% with 1 nM dexamethasone. Differentiation of murine monocytic and granulocytic colonies in agar from bone marrow precursors was decreased by 50% at 7 days with 20 nM dexamethasone. Secretion of elastase, collagenase, and plasminogen activator by resident and thioglycollate-elicited mouse peritoneal macrophages was decreased by dexamethasone, cortisol, and triamcinolone acetonide (1--1,000 nM), but not by progesterone, estradiol, and dihydrotestosterone (1,000 nM); in contrast, secretion of lysozyme was not affected by glucocorticoids or other steroids. The inhibition of macrophage secretion by dexamethasone was both time and dose dependent. Effects were detected within 1--6 h after addition of the glucocorticoids, became maximum by 24 h, and were reversed during a similar time period after removal of the hormones. The extent of inhibition of macrophage secretion increased with increasing glucocorticoid concentration. Half-maximum inhibition of secretion of elastase, collagenase, and plasminogen activator was seen at dexamethasone concentrations (1--10 nM) similar to those that half-saturated the specific glucocorticoid receptors in these cells. At high concentrations of dexamethasone (100--1,000 nM) the secretion of plasminogen activator was inhibited to a greater extent (greater than 95%) than the secretion of elastase (60--80%). Progesterone alone had no effect on secretion, but it blocked the inhibitory effects of dexamethasone and cortisol. Secretion of collagenase, neutral proteinases, and plasminogen activator by elicited rabbit alveolar macrophages was inhibited with glucocorticoids (0.1--100 nM) but not with progesterone or sex steroids. Secretion of a neutral elastinolytic proteinase by guinea pig alveolar macrophages was also inhibited by dexamethasone. These data support the regulatory role of glucocorticoids on macrophage functions at physiological concentrations.
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PMID:Biochemical actions of glucocorticoids on macrophages in culture. Specific inhibition of elastase, collagenase, and plasminogen activator secretion and effects on other metabolic functions. 21 Feb 48

Studies were conducted with chicken granulosa cells to evaluate the relative efficacy of human recombinant transforming growth factor alpha (TGF alpha) versus murine epidermal growth factor (EGF) to affect cyclic adenosine monophosphate (cAMP) accumulation and progesterone production stimulated by luteinizing hormone (LH) or steroid output induced by a cAMP analogue, and to modulate plasminogen activator (PA) activity. Increasing concentrations of EGF (33-328 nM) and TGF alpha (0.04-18 nM) were found to inhibit cAMP formation stimulated by LH in a dose-dependent manner, with calculated half-maximal inhibitory doses (ID50's) of 97.1 and 0.27 nM, respectively. Similarly, a 470-fold difference in the ability of TGF alpha (ID50 = 0.13 nM) versus EGF (ID50 = 61.3 nM) to half-maximally suppress LH-induced progesterone production was observed in the same cells. Progesterone production stimulated by a cAMP analogue (8-bromo-cAMP, 1 mM) was also attenuated by EGF (ID50 = 75.9 nM) and TGF alpha (ID50 = 0.08 nM), suggesting a post-cAMP site of inhibition by these growth factors on steroidogenesis. Finally, a 260-fold to 330-fold difference in the efficacy of TGF alpha versus EGF to half-maximally stimulate cell-associated and secreted PA activity was observed. From these data, we propose that TGF alpha may serve an important role in regulating follicular growth and maturation in the domestic hen via its ability to affect granulosa cell steroidogenesis and plasminogen activator activity.
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PMID:Modulation of hen granulosa cell steroidogenesis and plasminogen activator activity hy transforming growth factor alpha. 217 38

1. Regulatory mechanism of cell growth of endometriosis in comparison with endometrium. Estradiol alone has no growth-promoting effect on both endometriotic and endometrial cells. Epidermal growth factor (EGF) stimulates cell growth of both cell types. Endometrial cells but not endometriotic cells produce and release EGF into culture media so that stimulatory effect of exogenous addition of EGF is blunted in endometrial cells. Estradiol exerts its mitogenic action by enhancing the mitogenic effect of EGF in endometrium. By contrast, the effect of estradiol is minimal in endometriotic cells, showing less dependency on estradiol for their proliferation. Progesterone inhibits cell growth of the both cell types in the same manner. 2. A biological role of EGF in endometriosis. Endometriotic cells possess EGF receptors. The affinity of the receptor is the same as that of endometrial cells. However, the number of receptor per cell is about half of that for endometrium. Estradiol increases the number of EGF receptors in endometrial cells which may explain the mitogenic effect of estradiol in the face of EGF. However, stimulatory effect of estradiol for EGF receptors is less pronounced in endometriotic cells. Mitogenic action of EGF is suggested to be mediated by phosphorylation of tyrosine residues of 170 kd protein in the tissues. EGF increases the production of tissue plasminogen activator (t-PA) and activates the aromatase activity of the both cell types. However, the stimulatory action of EGF on progestin receptor is observed only in endometrial cells. 3. Biochemical characterization of endometriotic cells in comparison with endometrial cells. Endometriotic tissues accumulate less amount of glycogen and XIII factor of blood coagulation as compared to endometrial tissues. The ability of endometriotic cells to release prostaglandin is also weaker, suggesting suppressed differentiated function of endometriotic cell. Endometriotic cells produce the same amount of CA125 as endometrial cells. Danazol and EGF inhibit the release of CA125 into culture media when standardized per cell. Therefore, normalization of CA125 levels during the treatment dose not always mean the reduction of the lesions but reflect the suppressed function of the endometriotic tissues. 4. Altered microenvironment of endometriotic tissues. An analysis of peritoneal fluid. The amount of peritoneal fluid (PF) with endometriosis increased throughout the menstrual cycle. A number of macrophage is reported to increase in PF with endometriosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Fundamental and clinical studies on biochemical properties of endometriosis in comparison with endometrium]. 250 2

The main emphasis of this paper is on the changes in function of granulosa cells as they undergo cytodifferentiation in follicles developing from the preantral to the antral stage, and on the hormones present in the milieu of gonadotrophins and steroids which are essential for these events to proceed normally. We found that FSH alone could induce aromatase activity in cultures of immature granulosa cells and that this effect could be duplicated by dibutyryl cyclic AMP. Incubation of cell sonicates under optimal conditions indicated that FSH acted on granulosa cells to increase the cellular concentration of active aromatase. Prior treatment with androgens augmented the FSH effect. Progesterone synthesis is another differentiated function which can be induced in culture by FSH alone and augmented in the presence of androgens. In assessing the enzymes involved in progesterone synthesis we found that cholesterol side-chain cleavage activity had similar hormonal requirements whereas 3 beta-hydroxysteroid dehydrogenase activity was stimulated by FSH alone. FSH also stimulates cyclic AMP binding activity in cultured granulosa cells during cytodifferentiation. These proteins represent another class of intracellular proteins, quite distinct from the steroidogenic enzymes, which increase as the granulosa cells mature. The ability of FSH to induce the appearance of LH and prolactin receptors, and stimulate the secretion of plasminogen activator and proteoglycans is reviewed. It is concluded that the appearance of steroidogenic enzymes and other intracellular proteins, cell-surface and secreted proteins as well as morphological maturation of granulosa cells require the presence of FSH. In the "turning-on" of some of these differentiated functions androgens play a permissive role. Having established events which occur during normal development of the follicle, we considered ways by which this overall process could be interrupted and fertility controlled. Here we describe the ways by which prolactin and LHRH interfere with the normal process of granulosa cell cytodifferentiation.
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PMID:Hormonal interactions in the control of granulosa cell differentiation. 631 Feb 32

Multiple molecular forms of plasminogen activator were detected in normal human mammary epithelial cells in culture. Cells derived from (normal) breast mammoplasty specimens and grown on the surface of collagen gels exhibited three major classes of plasminogen activator isozymes (Mr = 100,000 [100K], 75,000 [75K], and 55,000 [55K]). The activity of the 100K and 75K isozymes was greatly reduced when the cells were grown on conventional tissue-culture-grade plastic surfaces. MCF-7, a human mammary carcinoma cell line, exhibited predominantly or exclusively the 55K isozyme, irrespective of the cell growth substratum. The activity of the 55K isozyme was more than twofold higher for MCF-7 cells grown on collagen gels than for cells grown on plastic. Progesterone, diethylstilbestrol, and estrogen stimulated the activity of the 55K isozyme of MCF-7 cells, but only when the cells were grown on a plastic surface. The plasminogen activator activities of the normal human mammary epithelial cells were not stimulated by these hormones, irrespective of the growth substratum. These results show that the expression of plasminogen activator isozymes by human mammary epithelial cells is subject to modulation by the extracellular matrix. Normal and malignant cells may differ in their responsiveness to these effects.
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PMID:Effect of the extracellular matrix on plasminogen activator isozyme activities of human mammary epithelial cells in culture. 668 79

Variations in the production of plasminogen activator (PA), a proteolytic enzyme that has been associated with trophoblast invasiveness, may be critical to the success or failure of placentation. To understand better the mechanisms regulating PA production we have cultured human trophoblast cells and measured the effect of steroid hormones and protein synthesis inhibitors upon their capacity to lyse 125I-fibrinogen. Progesterone (P) and 17 beta-estradiol (E2) at concentrations of 10(-8)M, 10(-7)M, and 10(-5)M did not cause significant changes in PA or chorionic gonadotropin (hCG) production by the trophoblast cells. In contrast, dexamethasone (10(-8)M and 10(-5)M) caused a significant, dose-dependent decrease in PA production. There was no significant difference in PA and hCG production between trophoblast cultures treated with cytosine arabinoside (1 mg/ml) and untreated cultures. When actinomycin D (0.5 microgram/ml) was added to cultures at time zero, the production of PA and hCG during the first 24 hours of incubation was not significantly different from that of untreated cultures. After 24 hours, however, PA and hCG disappeared from the actinomycin-treated cultures while both substances continued to be released in the untreated controls. These experiments indicate that trophoblastic PA and hCG production in vitro are independent of DNA replication and not under P or E2 control. They also show that PA and hCG are stored within the trophoblast cells and released into the medium during the first 24 hours of incubation; after this period the presence of PA and hCG in the medium represents de novo synthesis. The data also suggest that, similar to hCG, PA is produced continuously in vitro as long as the trophoblast cell is functionally active.
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PMID:Plasminogen activator production by trophoblast cells in vitro: effect of steroid hormones and protein synthesis inhibitors. 719 56

In a primary human endometrial cell culture, the addition of progesterone resulted in an approximately 2-fold increase in the amount of tissue-type plasminogen activator (t-PA) released into the culture media, with the minimal effective dose being 10(-7) M. In contrast, progesterone significantly reduced the release of urokinase-type PA (u-PA). Endometrial cells are known to release a major PA inhibitor, PAI-1. Progesterone stimulated the release of PAI-1. These observed effects of progesterone seem to be mediated through the progestin receptor in that R5020, a specific ligand for progestin receptor, mimicked the effects of progesterone, and RU486, an antagonist of progesterone, completely eliminated the effects of progesterone. It is notable that estradiol, when added alone or in combination with progesterone, caused no discernible effect on the release of PAs and PAI-1. These results suggest that progesterone is a key hormone in regulating the PA/plasmin system in the human endometrium, thereby playing a pivotal role in implantation and ensuing embryonal development.
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PMID:Effects of steroid hormones on fibrinolytic system in cultured human endometrial cells. 759 99

Progesterone acts on the estradiol (E2)-conditioned human endometrium to induce decidualization of stromal cells. Consistent with these differential hormone actions in vivo, progestins regulate several end points of decidualization in human endometrial stromal cell monolayers, and E2 augments the effects of progestin. This study shows that in vitro decidualization of the stromal cells is accompanied by diminished plasminogen activator (PA) expression. Polyacrylamide gel electrophoretic separation after immunoprecipitation of biosynthetically labeled PAs revealed that medroxyprogesterone acetate (MPA) lowered levels of secreted tissue type PA (tPA) at 67 kilodaltons and urokinase type PA (uPA) at 55 kilodaltons. These levels were reduced further by E2 plus MPA despite a lack of response to E2 alone. Although tPA activity was readily measured by a chromogenic assay, detection of uPA activity required prior activation, indicating that uPA is released as the pro-uPA zymogen. Comparisons of levels of immunogenic PAs, as measured by specific enzyme-linked immunosorbent assays, with the corresponding catalytic activities revealed selective progestational inhibition of PA activity vs. antigen after 3 days of experimental incubation. Thus, 10(-7) mol/L MPA produced about a 2-fold greater reduction of levels of PA activity than that of its corresponding antigen. More strikingly, 10(-8) mol/L E2 plus 10(-7) mol/L MPA virtually eliminated both tPA activity (99% inhibition; P < 0.005) and uPA activity (93% inhibition; P < 0.005); the reductions in levels of the corresponding antigens were only about 50% of the control levels and did not attain statistical significance. Only after 3-6 days of incubation with E2 plus MPA was statistically significant inhibition achieved for immunogenic levels of both tPA (P < 0.05) and uPA (P < 0.005). Preferential inhibition of levels of PA activities compared with those of the corresponding PA antigens reflects the action of the potent PA inhibitor PAI-1. Thus, the concentration of PAI-1 in the stromal cell-conditioned medium at the end of 0-3 days exceeded those of tPA and uPA, respectively, by 28- and 12-fold in response to MPA and by 52- and 25-fold in response to E2 plus MPA. Extrapolation of these in vitro results to the events of the luteal phase, whose steroidal milieu is mimicked by E2 plus MPA, indicates that decidual cell-derived PAI-1 is a key regulator of proteolytic degradation of extracellular matrix and fibrinolysis during implantation and menstruation.
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PMID:Plasminogen activator activity during decidualization of human endometrial stromal cells is regulated by plasminogen activator inhibitor 1. 762 51

Progesterone stimulates differentiation and inhibits the growth of endometrial tissue. Also, progesterone reduces plasminogen activator (PA) activity, which implies reduced turnover of extracellular matrix proteins in the secretory phase. To elucidate the mechanism responsible for reduced PA activity, primary cultures of human endometrial stromal cells were stimulated with estradiol and progesterone. Conditioned media were assayed for urokinase-type and tissue-type PA (u-PA and t-PA, respectively), PA inhibitor-1 (PAI-1), and PA activity. Binding of [125I]u-PA and [125I]u-PA:PAI-1 complex to the u-PA receptor and clearance of these ligands were studied. The PA activity of conditioned medium decreased after stimulation with progesterone, and this was secondary to a decrease in u-PA, but not t-PA, and an increase in PAI-1. Northern blot analysis showed induction of PAI-1 messenger ribonucleic acid, whereas the content of u-PA messenger ribonucleic acid was not influenced. Furthermore, the number of free u-PA receptor-binding sites was increased by estradiol and progesterone. The stromal cells degraded complexed u-PA more efficiently than free u-PA, and degradation of both ligands was inhibited by colchicine, chloroquine, and methylamine. Degradation was increased after hormone treatment, and this was apparently due to increased ligand binding, because neither ligand affinity nor the relative rate of degradation was increased. Increased expression of u-PA receptor-binding sites was not regulated on the transcriptional level, but may result from posttranslational mechanisms, such as decreased turnover of the receptor. Activation of plasminogen by receptor bound u-PA initiates a cascade of proteolytic events in the extracellular matrix that is important during tissue proliferation. Our data suggest that differentiated endometrial stroma in the secretory phase regulates extracellular proteolysis by increased elimination of u-PA through increased release of PAI-1 and increased u-PA receptor density.
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PMID:Progesterone stimulates degradation of urokinase plasminogen activator (u-PA) in endometrial stromal cells by increasing its inhibitor and surface expression of the u-PA receptor. 767 23

The first generation high-dose ( 80 mcg estrogen) oral contraceptives (OCs) were associated with an increased risk of deep venous thrombosis (DVT). So manufacturers removed the high-dose OCs and first replaced them with OCs with 50 mcg estrogen, resulting in a lower incidence of thromboembolic events (40 vs. 20/100,000 users). When they introduced an even lower dose OC (30 mcg estrogen), the incidence fell further (about 8/100,000 users). Yet, women using the lowest-dose OCs still have DVT more often than do control women. Life-style, age, and smoking may be confounding factors, however. It is not clear whether loss of endogenous ovarian steroid production or the effects of the orally administered contraceptive steroids cause significant changes in hemostatic factors (antithrombin III, protein S, protein C, plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor 1, histidine-rich glycoprotein, and VII, VIII, X, XII coagulation factors) during OC use. These changes tend to be within normal ranges. There is some doubt that these changes have any clinical significance. In nonsmokers, increased activity of anticoagulant factors and fibrinolytic factors counteract the effects on coagulation factors. Progestin-only OCs appear to affect hemostasis but have not increased the risk of thrombosis. There are considerable differences between people in pharmacokinetics and pharmacodynamics of contraceptive steroids. These differences may account for the increased risk of thromboembolic events in some people. Further research should identify methods of individualizing the dose of contraceptive steroids for a single patient. It should also explore the close interrelationship between hemostasis and lipid metabolism, carbohydrate metabolism, and hypertension in the development of cardiovascular disease in OC users. Providers should discourage women with a past history of DVT from using hormonal contraception.
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PMID:Coagulation and anticoagulation effects of contraceptive steroids. 817 1


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