Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells can release arachidonic acid (AA) metabolites as well as preformed mediators with IgE mediated stimulation, and these mediators are considered to play an important role in allergic reactions. The coincident release of preformed mediators and AA metabolites suggests that AA metabolism is related to mast cell degranulation. To clarify the relationship between mast cell degranulation and AA metabolism, the effects of various A cascade inhibitors on rat basophilic leukemia cell (RBL) mediator release induced by either anti-IgE or A23187 were examined. 5,8,11,14-eicosatetraynoic acid (ETYA) inhibited both PGD2 and LTC4/D4 generation, and partially inhibited serotonin release. Nordihydroguaiaretic acid (NDGA) caused complete inhibition of LTC4/D4 generation, and partial inhibition of PGD2 generation and serotonin release. The cyclooxygenase inhibitor, indomethacin, and the specific 5-lipoxygenase inhibitor, L-651,392 completely inhibited PGD2 and LTC4/D4 generation, respectively, without affecting release of other mediators. Both PGD2 and LTC4/D4 generation were abolished by the combination of indomethacin and L-651,392, however, serotonin release remained intact. HPLC analysis showed that no shift to other AA metabolites occurred after the treatment with these inhibitors. Mepacrine, a phospholipase A2 inhibitor, completely inhibited PGD2 and LTC4/D4 generation, as well as AA release itself, without affecting serotonin release. Therefore, neither AA metabolism nor AA release is necessary for RBL degranulation.
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PMID:Effects of inhibitors of arachidonic acid metabolism on serotonin release from rat basophilic leukemia cells. 850 Sep 85

Mast cells play a key role in inflammatory reactions triggered by tissue injury or immune perturbations. Little is known about endogenous molecules and mechanisms capable of modulating inappropriate mast cell activity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), found in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation-hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Recently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agonist at the peripheral cannabinoid CB2 receptor. Here, we have characterized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given orally in a battery of rodent models of inflammation. LG 2110/1 diminished, in a dose-dependent and correllated manner, the number of degranulated mast cells and plasma extravasation induced by substance P injection in the mouse ear pinna. In addition, LG 2110/1 reduced dose dependently plasma extravasation induced by passive cutaneous anaphylaxis reaction. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholipase A2-induced hindpaw edema. Further, anti-edema effects were observed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in minimizing dextran-induced hind paw edema. In contrast, equivalent amounts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plasma extravasation induced by the substance P fragment, substance P-(6-11), known to be inactive on mast cells. These results indicate that orally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides ('ALIAmides') represent novel therapeutic agents useful in the management of inflammatory disease conditions.
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PMID:N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. 873 13

Antigen stimulation of mast cells via the IgE receptor, Fc epsilon RI, results in recruitment of the cytosolic tyrosine kinases, Lyn and Syk, and the phosphorylation of proteins. We examined the effects of the glucocorticoid dexamethasone on these events in a cultured (RBL-2H3) mast cell line. Nanomolar concentrations of dexamethasone suppressed phosphorylation of proteins that were associated with the activation of the mitogen-activated protein (MAP) kinase/phospholipase A2 pathway without inhibiting initial events. For example, tyrosine phosphorylation of the subunits of Fc epsilon RI, Lyn, or Syk or of the Ras-guanine nucleotide exchange factor, Vav, was not suppressed in cells treated with up to 1 microM dexamethasone. In contrast, phosphorylation of Raf1, MEK1, p42mapk, and cytosolic phospholipase A2, as well as the associated increase in MAP kinase activity and release of arachidonic acid, were markedly inhibited in cells treated with as little as 10 nM dexamethasone--a concentration that only partially inhibited hydrolysis of inositol phospholipids or release of secretory granules. Prolonged exposure to dexamethasone also resulted in a partial decrease in expression of MEK1, p42mapk, and cytosolic phospholipase A2, which may contribute further to the effects of dexamethasone on this pathway. Activation of the MAP kinase/phospholipase A2 pathway by the calcium-mobilizing agent thapsigargin was similarly suppressed in dexamethasone-treated cells. These findings suggested that an early step in the pathway, possibly a step immediately before the activation of Raf1, was suppressed by low concentrations of dexamethasone.
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PMID:Activation of the mitogen-activated protein kinase cascade is suppressed by low concentrations of dexamethasone in mast cells. 880 35

A number of structurally diverse antigens preferentially stimulate the synthesis of IgE antibodies, but no unifying principle has been proposed that explains the nature of isotype selection. In the present study, we show that common allergens present in bee venom, house dust mite emanations and parasite proteins induce mast cell and basophil degranulation and stimulate interleukin-4 synthesis, and secretion in the absence of antigen-specific IgE. These data point to a linkage between the initial activation of cells of the innate immune system and subsequent adaptive immune responses. They suggest that IgE-independent mast cell and basophil degranulation is predictive of potential allergenicity and can be evaluated by means of a cellular assay. Our study indicates that non-immunological degranulation by prototypic allergens, such as bee venom phospholipase A2 or proteases associated with house dust mite emanations, is critically dependent on enzymatic activity. These findings have potentially important implications for vaccine design in allergic and parasitic disease.
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PMID:Potential allergens stimulate the release of mediators of the allergic response from cells of mast cell lineage in the absence of sensitization with antigen-specific IgE. 897 93

Aggregation of IgE cell surface receptors on MMC-34 cells, a murine mast cell line, induces the synthesis and secretion of prostaglandin D2 (PGD2). Synthesis and secretion of PGD2 in activated MMC-34 cells occurs in two stages, an early phase that is complete within 30 min after activation and a late phase that reaches a maximum about 6 h after activation. The early and late phases of PGD2 generation are mediated by prostaglandin synthase 1 (PGS1) and prostaglandin synthase 2 (PGS2), respectively. Arachidonic acid, the substrate for both PGS1 and PGS2, is released from membrane phospholipids by the activation of phospholipases. We now demonstrate that in activated mast cells (i) secretory phospholipase A2 (PLA2) mediates the release of arachidonic acid for early, PGS1-dependent synthesis of PGD2; (ii) secretory PLA2 does not play a role in the late, PGS2-dependent synthesis of PGD2; (iii) cytoplasmic PLA2 mediates the release of arachidonic acid for late, PGS2-dependent synthesis of PGD2; and (iv) a cytoplasmic PLA2-dependent step precedes secretory PLA2 activation and is necessary for optimal PGD2 production by the secretory PLA2/PGS1-dependent early pathway.
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PMID:Prostaglandin synthase-1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cells. 901 59

Prostaglandin D2 (PGD2) synthesis in activated mast cells occurs in two phases, an early phase that is dependent on prostaglandin synthase 1 and a delayed phase that is dependent on activation-induced prostaglandin synthase 2 gene expression. Early phase PGD2 synthesis in activated mast cells also requires the activity of a secretory phospholipase A2 (PLA2). It has been thought that the secretory PLA2 expressed in mast cells is group IIa PLA2, encoded by the Pla2 g2a gene. However, activated bone marrow-derived mast cells prepared from Pla2 g2a+/+ mice and mast cells prepared from mice with a mutation in the Pla2 g2a gene both demonstrate early phase PGD2 synthesis. Moreover, mast cells from both murine strains secrete PLA2 activity following activation. Northern and reverse transcriptase/polymerase chain reaction analyses demonstrate that mast cells from Pla2 g2a+/+ and Pla2 g2a-/- mice do not express group IIa PLA2 message. Instead, Northern and reverse transcriptase/polymerase chain reaction analyses demonstrate that both Pla2 g2a+/+ and Pla2 g2a-/- mast cells express mRNA for group V PLA2, encoded by the Pla2gV gene. An antisense oligonucleotide directed against group V PLA2 is also able to inhibit both the early phase of PGD2 production and the secretion of PLA2 activity by activated mast cells. Our data suggest that (i) group IIa PLA2 does not play a significant role in murine mast cell prostaglandin synthesis, (ii) group V PLA2 mediates early mast cell PGD2 production and transcellular PGE2 production in murine mast cells, and (iii) much of the data, based on studies with chemical inhibitors and antibodies, suggesting that group IIa PLA2 is responsible for arachidonic acid mobilization needs to be reevaluated.
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PMID:Analysis of the secretory phospholipase A2 that mediates prostaglandin production in mast cells. 915 7

Bothropstoxin-I and bothropstoxin-II are phospholipase A2 homologues isolated from Bothrops jararacussu snake venom. The former is devoid of phospholipase A2 activity whereas the latter has very low enzymatic activity. In this study, we have investigated the in vivo (rat paw and skin oedema) and in vitro (mast cell degranulation) inflammatory effects caused by bothropstoxin-I and bothropstoxin-II. Bothropstoxin-I (25-100 microg/paw) and bothropstoxin-II (12.5-50 microg/paw) caused dose-dependent rat paw oedema. The intradermal injection of bothropstoxin-I (0.125-5 microg/site) and bothropstoxin-II (0.125-5 microg/site) into rat skin also resulted in dose-dependent oedema formation. These oedematogenic activities were largely reduced in animals pretreated with the histamine/5-hydroxytryptamine (5-HT) receptor antagonist cyproheptadine (2 mg/kg, i.p. 0.5 h before). Similarly, p-bromophenacyl bromide, a compound known to inhibit phospholipase A2 activity, significantly inhibited rat paw and skin oedema induced by both phospholipase A2 homologues. The polyanion heparin (5 IU/site) significantly reduced the rat skin oedema induced by either bothropstoxin-I or bothropstoxin-II as well as the paw oedema (50 IU/site) induced by the former. When assayed in the rat peritoneal mast cells in vitro, both bothropstoxin-I (10 and 100 microg/ml) and bothropstoxin-II (3 and 10 microg/ml) significantly caused [14C]5-HT release. The [14C]5-HT release caused by these phospholipase A2 homologues were reduced by p-bromophenacyl bromide and heparin (50 IU/ml). Our results indicate that oedema formation induced by bothropstoxin-I and bothropstoxin-II is mostly dependent on in vivo mast cell degranulation. Since heparin greatly reduced the oedematogenic activity of these phospholipase A2 homologues, it is likely that the cationic charge of these substances plays a major role in the mast cell activation. Our results also indicate that p-bromophenacyl bromide may not be a suitable pharmacological tool to investigate the correlation between enzymatic activity and the inflammatory effects of phospholipases A2.
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PMID:Mast cell degranulation induced by two phospholipase A2 homologues: dissociation between enzymatic and biological activities. 957 Apr 75

The current study examined mechanisms that account for the selective release of arachidonic acid (AA) from cells by secretory phospholipase A2 (sPLA2). Initial studies demonstrated that low concentrations of group I and group III PLA2 isotypes and an sPLA2-enriched extract from bone marrow-derived mast cells (BMMC) selectively released AA from mast cells. Much higher concentrations of group II PLA2 were required to release comparable quantities of AA. Group I PLA2 also selectively released AA from another mast cell line (CFTL-15) and a monocytic cell line (THP-1). In contrast, high concentrations of group I PLA2 were required to release fatty acids from a promyelocytic cell line (HL-60) and this release was not selective for AA. Binding studies revealed that cell types (BMMC, CFTL-15 and THP-1) which selectively released AA also had the capacity to specifically bind group I PLA2. However, group II PLA2, which did not selectively release AA from cells, also did not specifically bind to these same cell types. Additional studies revealed that sPLA2 binding to the mast cell receptor was attenuated after stimulation with antigen or ionophore A23187. Reverse transcriptase-polymerase chain reaction analyses indicated the presence of mRNA for the sPLA2 receptor in BMMC, CFTL-15 and THP-1 and the absence of this mRNA in HL-60. Final studies demonstrated that p-aminophenyl-alpha-D-mannopyranoside BSA, a known ligand of the sPLA2 receptor, also selectively released AA from mast cells but not from HL-60 cells. These experiments indicated that receptor occupancy alone (without PLA2 activity) is sufficient to induce the release of AA from mast cells. Together, these data reveal that specific isotypes of sPLA2 have the capacity to selectively release AA from certain cells by their capacity to bind to sPLA2 receptors on the cell surface.
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PMID:Mechanisms that account for the selective release of arachidonic acid from intact cells by secretory phospholipase A2. 974 13

Rat peritoneal mast cells are stimulated to generate superoxide anion (O2) by the addition of compound 48/80 and A23187. Recently, we demonstrated by immunohistochemical and Western blot analysis that the mast cells contained the p47phox protein, which was one of cytosolic component of the NADPH oxidase system. In the present study, it was demonstrated that the mast cells contained the p47phox mRNA, much similar to that of mouse leukocyte. The permeabilized mast cells were stimulated to generate O2- by the addition of Ca2+, phospholipase A2 (PLA2) and arachidonic acid. Our data suggest the following:(1) cytosolic PLA2 may be activated by the elevation of [Ca2+]i; (2) the conjugation of membrane component with cytosolic component may be stimulated by the released arachidonic acid. The mast cell granules contained superoxide dismutase (SOD)-like enzyme, which degradated O2-, generated in xanthine-xanthinoxidase system. SOD-like enzyme was released from the granules by the treatment with Ca2+ and trapped by the treatment with heparin. In conclusion, our studies suggest that the disorder of the degradation system of O2- may contribute to the development of allergic inflammation.
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PMID:[Role of superoxide generation and degradation system of mast cells in allergic inflammation]. 1019 Jan 38

The activation of endogenous pancreatic enzymes during automated pancreas digestion may be detrimental to islet isolation. In this report we assessed the activation of trypsin, chymotrypsin, elastase, carboxypeptidases A and B, phospholipase A2, and lipase using a porcine model. Four islet isolations were examined. Duplicate aliquots were taken from the automated circuit at 5-min time intervals up to the completion of pancreas digestion (approx 60 min). One aliquot was activated in vitro with exogenous trypsin in order to convert the enzymes into their active non-"proform," with the exception of trypsinogen, which was activated with exogenous enterokinase. This was done to assess the percentage activation of each individual enzyme (total potentially activatable enzyme release). The extent of activation between isolations was extremely variable. During the closed (recirculating) circuit phase of pancreas digestion there were both gradual and rapid increases in the levels of enzymes released. Peak activity of enzyme activation varied from 13 to 30 min; similarly, total potentially activatable peaks occurred between 13 and 38 min. Lipase and carboxypeptidase B showed greater than 70% activation, chymotrypsin, carboxypeptidase A, and phospholipase A2 between 50% and 70% activation, and trypsin and elastase less than 20%. There were up to 30-fold differences between the four islet preparations. In summary, it is unlikely that poor islet yields are soley explained by variations between collagenases; the variable activation of endogenous pancreatic exocrine enzymes is also likely to be influential to porcine islet yields.
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PMID:A preliminary study of the activation of endogenous pancreatic exocrine enzymes during automated porcine islet isolation. 1044 39


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