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)

The production of collagenase (EC 3.4.24.3) by endotoxin-stimulated macrophages was significantly inhibited by indomethacin, indicating that prostaglandins (PGs) mediate this effect. Inhibitions of collagenase production by indomethacin was overcome by addition of exogenous PGE2 at 10 nM whereas the addition of 0.1 and 1.0 micrometer PGE2 increased the enzyme production to 3 times that achieved by endotoxin. Although the addition of prostaglandin alone to macrophage cultures did not stimulate collagenase production, the simultaneous addition of PGE1 or PGE2 and endotoxin enhanced collagenase activity 2- to 10-fold. This increase was detectable at PGE concentrations of 10 nM and was optimal at 0.1-1.0 micrometer. PGF2alpha had little effect on either the enhancement of collagenase production by endotoxin-stimulated macrophages or its restoration in cultures inhibited by indomethacin. Radioimmunoassay of prostaglandins in the culture media revealed that macrophages exposed to endotoxin secreted 40-fold more PGE2 than did unstimulated cells. The increase in PGE2 was detected 4 hr after exposure to endotoxin and was maximal at 14 hr. The peak PGE2 concentrations in the culture media were similar to those of exogenous PGE2 (about 10 nM) needed to restore collagenase production in indomethacin-treated cultures. These findings demonstrate the involvement of PGE in the endotoxin-activation of macrophages with resultant production of collagenase.
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PMID:Prostaglandin regulation of macrophage collagenase production. 20 Sep 41

Selected properties of [3H]prostaglandin (PG) E1 binding to collagenase dispersed bovine luteal cells were studied and compared with those observed in luteal plasma membranes. [3H]-PGE1 specific binding to a relatively homogeneous population of luteal cells was a rapid (K1 = 4.2 X 10(5) M-1 .sec-1), reversible (K-1 = 3.9 X 10(-3) sec-1), saturable and specific process at 38 degrees C. The binding was homogeneous with an apparent dissociation constant of 2.4 nM and 1.8 X 10(5) receptors per cell. The presence of increasing amounts of unlabeled PGs inhibited [3H]PGE1 binding in a dose-dependent manner. The potency order for this inhibition of binding was: PGE 2 greater than PGE1, (15S)-15-methyl-PGE2 methyl ester greater than PGF2alpha greater than PGF1alpha greater than other PGs, PGE, PGF metabolites and PGF analogs. Other than the homogeneous nature of [3H]PGE1 binding and the greater effectiveness of PGE2 compared to PGE1 in cells, the rest of the properties of [3H]PGE1 binding to cells were in excellent agreement with those observed in plasma membranes.
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PMID:Selected properties of [3H]prostaglandin E1 binding to dispersed bovine luteal cells. 20 3

Adenylate cyclase activity in particulate fractions from a transplantable rat osteogenic sarcoma was stimulated in a dose-dependent manner by prostaglandins E1 and E2 (PGE1 and PGE2) and parathyroid hormone (PTH). Prostaglandin F2alpha was active at a high concentration (3 x 10(-4) mol/l). Pretreatment of membranes with collagenase plus hyaluronidase reduced the magnitude of the PTH effect but did not affect the size of the PGE1 effect. Guanosine 5'-triphosphate and its synthetic analogue 5'-guanylylimidodiphosphate (Gpp(NH)p) activated adenylate cyclase in particulate preparations from the osteogenic sarcoma. The latter agent produced much larger effects, although the concentrations required for half-maximal enzyme activation were the same for both agonists (approximately 2 x 10(-6) mol/l). The effects of PTH and Gpp(NH)p were supra-additive at some concentrations of hormone. The effects of PGE1 and Gpp(NH)p were supra-additive at all hormone concentrations tested. Pre-incubation of membrane particles for 6 min with PTH produced an enzyme activation which was not reversed by dilution through washing; pre-incubation with PGE1 did not produce this effect. The response of membrane adenylate cyclase to Gpp(NH)p (10(-4) mol/l) was 75% greater in preparations pre-incubated with PTH than in membranes pre-incubated in buffer alone or in buffer containing PGE1. The basal rate of cyclic AMP production in the adenylate cyclase assay system decreased over a 35 min incubation period. This decrease was prevented by addition of PTH or PGE1. Addition of NaF or Gpp(NH)p produced a steady increase in the rate of production of cyclic AMP with time. Membrane preparations did not reduce the biological activity of PTH and did not degrade 125I-labelled PTH. The results demonstrate that the PTH- and PGE-responsive adenylate cyclases of the osteogenic sarcoma have distinctly different properties and that particulate preparations of the tumour do not metabolize PTH.
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PMID:Membranes from a transplantable osteogenic sarcoma responsive to parathyroid hormone and prostaglandins: regulation of adenylate cyclase and of hormone metabolism. 27 36

Whether toxic or immunomodulatory factors are released during the collagenase digestion phase of the isolation of mononuclear cells from human intestinal mucosa was investigated by assessing the effect of the collagenase supernatant on the viability and natural killer activity of normal peripheral blood mononuclear cells. Three hours' incubation in collagenase supernatant suppressed natural killer activity by 25 +/- 4% and decreased the viability of peripheral blood mononuclear cells by 11 +/- 2%. The ability of collagenase supernatants to kill 51Cr-labelled peripheral blood mononuclear cells over four hours was assessed in 16 collagenase supernatants, eight of which produced lysis of 20 +/- 4%. There was no ultrastructural evidence of early degenerative changes in the viable intestinal mononuclear cells fresh from the isolation process or in peripheral blood mononuclear cells incubated in collagenase supernatant. Because prostaglandins are known to inhibit natural killer activity, PGE was measured in 20 collagenase supernatants by radioimmunoassay and found to be high at 27.5 +/- 4.0 ng/ml. Addition of indomethacin to the collagenase medium, however, failed to abolish the inhibitory effect of collagenase supernatant on natural killer activity and did not increase the natural killer activity of isolated intestinal mononuclear cells. The release of cytotoxic and immunomodulatory factors during the isolation of intestinal mononuclear cells indicates the necessity for careful assessment of the potential effects of the isolation process on any function being examined and casts doubt upon the relationship between in vitro findings and in vivo functional capabilities.
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PMID:Isolation of intestinal mononuclear cells: factors released which affect lymphocyte viability and function. 298 Nov 88

Activation of macrophages results in the production of tissue destructive mediators and enzymes including prostaglandins (PGE) and collagenase. In addition, activated macrophages also generate mediators which enhance connective tissue formation through their effects on fibroblast growth. To determine whether the pro-inflammatory mediators and the mediator(s) involved in tissue repair are under the same regulatory control, guinea pig macrophage cultures were treated with various pharmacologic agents and their supernatants monitored for biologic activity. The nonsteroidal anti-inflammatory agent, indomethacin, and the glucocorticoid, dexamethasone, at pharmacologic concentrations inhibited not only prostaglandin synthesis (greater than 90%) but also the production of collagenase (greater than 90%). Colchicine, a microtubule disruptive agent, but not the inactive form, lumicolchicine, markedly diminished the production of collagenase independently of prostaglandin synthesis. In contrast to the inhibitory effects of these anti-inflammatory agents on PGE and collagenase production, indomethacin did not inhibit the production of macrophage-derived fibroblast-activating factor (FAF). Furthermore, dexamethasone at pharmacologic doses did not inhibit FAF production. Colchicine not only did not inhibit FAF, but frequently enhanced the appearance of FAF In the macrophage cultures. Thus, it appears that regulation of the production of PGE and collagenase is different than the regulation of FAF synthesis and therefore the production of these mediators can be differentially modulated. Such a dissociation may provide a basis for mononuclear cell-mediated fibroblast growth and tissue repair to occur independently of the release of PGE2 and collagenase and even following anti-inflammatory drug therapy.
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PMID:Regulation of macrophage collagenase, prostaglandin, and fibroblast-activating-factor production by anti-inflammatory agents: different regulatory mechanisms for tissue injury and repair. 298 53

Metabolic heterogeneity has previously been demonstrated for cloned fibroblast populations. It is unclear whether a "high producer" or "activated" phenotype for one cell product reflects general metabolic activation or whether activated phenotypes for different metabolic markers segregate independently among cloned populations. We examined human foreskin fibroblast substrains, isolated by limiting dilution cloning, for heterogeneity in biosynthesis of PGE2 and collagenase (stimulated by Interleukin 1-containing mononclear cell supernates), and tissue factor. Synthesis of these products varied 5- to 10-fold among 16 substrains isolated from two parent lines (AT and WB). Metabolic phenotypes (high versus low levels of synthesis) were stable for the substrains over multiple weeks of culture. In neither group of substrains was there a correlation between levels of stimulated PGE synthesis and stimulated collagenase synthesis (r = -0.24 and 0.29 for AT and WB substrains, respectively). Similarly, tissue factor generation did not correlate with either PGE production (r = 0.12 and -0.38 for AT and WB substrains, respectively) or collagenase synthesis (r = 0.17 and 0.21 for AT and WB substrains, respectively). The discordance between high producer phenotypes for the different products was observed even when all three products were measured in the same culture. Activated phenotypes for different metabolic markers thus appear to segregate among cells independently. The process of connective tissue activation by immune cell-derived mediators may depend on the constituent makeup of the responding connective tissue cell population.
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PMID:Synthesis of PGE2, collagenase and tissue factor by fibroblast substrains: substrains are differentially activated for different metabolic products. 300 12

Osteoclastic (OC) and osteoblastic (OB) cells were isolated by sequential collagenase digestions of new-born rat calvaria. Prostaglandin E2(PGE2) did not alter total calmodulin levels after a 5 or 60 min incubation. The calmodulin antagonists, trifluoperazine (TFP) at 10-50 microM and W-7 (50 microM) inhibited PGE2-induced increases in calcium uptake by OC cells, but had no effect on control OC or OB calcium levels. W-5 (50 microM), a chlorine-deficient analogue of W-7 with weak anti-calmodulin activity, had no effect. Compound 48/80 (100-500 micrograms/ml), a highly effective calmodulin antagonist in other systems, had no effect on PGE2-induced calcium levels or control calcium uptake. There was inhibition of PGE2-induced increases in cyclic AMP by compound 48/80 (100 micrograms/ml) in both OC and OB cells but no effect on control levels. TFP at 50 microM inhibited both control and PGE2-induced increases in cyclic AMP but at 10 microM it lessened only the hormone-induced effect. W-7 (100 microM) inhibited PGE2-induced increases in OC and OB cyclic AMP but had no effect on control levels; W-5 (50 microM) had no effect on either of these. Dibutyryl cyclic AMP had no effect on control calcium uptake, PGE2-induced increases or W-7 inhibition of the PGE-2 effect on calcium uptake. The calmodulin antagonists, at doses which had affected only PGE2-induced increases in calcium uptake and/or cyclic AMP production, had no effect on leucine uptake by OC or OB cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of calmodulin antagonists on prostaglandin E2-induced responses in rat calvarial bone cells. 301 87

Interleukin 1 (IL 1), a cytokine expressed from a number of cell types, plays a vital part in immune and inflammatory processes. Epidermal IL1-like activity, also known as epidermal cell thymocyte-activating factor (ETAF), is associated with whole skin, epidermis, Langerhans cells and cultured keratinocytes and keratinocyte cell lines. We show that preparations of heat-separated epidermis possess abundant IL1/ETAF activity as indicated by PGE/collagenase induction in cultured synovial cells and proliferation of mouse thymocytes. However, using cDNA probes to interleukin-1 alpha and beta we show that freshly isolated heat-separated epidermis from healthy adult donors contains only a slight detectable level of IL1 alpha mRNA by dot blot analysis and no IL1 beta and IL1 alpha mRNA by Northern blot analysis. The implications of these observations will be discussed.
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PMID:IL1/ETAF activity and undetectable IL1 beta mRNA and minimal IL1 alpha mRNA levels in normal adult heat-separated epidermis. 326 28

The production of collagenase by lipopolysaccharide-(LPS) activated guinea pig macrophages is mediated by prostaglandins (PG) of the E series. After stimulation of guinea pig macrophages with LPS, extracellular PGE levels and cellular cAMP levels are elevated. Indomethacin inhibits not only PG synthesis, but also cAMP and collagenase production in LPS-stimulated macrophage cultures. In these indomethacin-inhibited cultures containing LPS, dibutyryl (dB) cAMP, or cholera toxin can restore macrophage collagenase production but not PG synthesis. Moreover, dBcAMP and cholera toxin enhance collagenase production in LPS-activated cultures. Initial activation of the macrophages by an agent such as LPS is a prerequisite for synthesis of collagenase, since in the absence of LPS, dBcAMP or cholera toxin alone are ineffective stimuli. These findings clearly demonstrate a role for PG-induced elevations of cAMP in the production of collagenase by LPS-activated macrophages.
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PMID:Mediation of macrophage collagenase production by 3'-5' cyclic adenosine monophosphate. 624 42

The effects of alterations in extracellular calcium concentration on prostaglandin (PGE) and thromboxane (TXB2) syntheses were studied in isolated epithelial cells from the urinary bladder of the toad, Bufo marinus. In epithelial cells prepared using collagenase, basal iPGE synthesis was greater than iTXB2 synthesis. Increasing extracellular calcium from zero to 1 mM increased iPGE synthesis and decreased iTXB2 synthesis equivalently such that total conversion of endogenous arachidonate to these two metabolites was unaltered. Vasopressin stimulated iPGE and iTXB2 syntheses when the incubation buffer contained 1 mM calcium but had no effect in the presence of 0.4 microM calcium. In contrast, using an EDTA isolation method, basal iPGE and iTXB2 syntheses were equal in the presence of zero calcium. Increasing extracellular calcium concentration to 1 mM caused a greater enhancement in iTXB2 synthesis compared to iPGE. Increasing extracellular calcium to 2 mM was associated with a decline in iPGE and iTXB2 syntheses back to the levels observed with no calcium added to the medium. The effect of increasing the calcium concentration was greater in phosphate than in bicarbonate buffer. In a Tris buffer the effect of altered calcium was almost completely abrogated. These studies demonstrate that the choice of buffer and alterations in extracellular calcium concentration differentially alter basal arachidonic acid metabolism to prostaglandins and thromboxane in isolated toad urinary bladder cells. The results suggest that there may exist several endogenous pools of arachidonic acid which are differentially influenced by calcium. Furthermore, the pool sensitive to vasopressin has an absolute requirement for calcium.
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PMID:Alterations in extracellular calcium concentration differentially influence prostaglandin and thromboxane synthesis in epithelial cells from the toad urinary bladder. 642 55


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