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)

Biochemical mechanisms of desensitization were explored by using peritoneal mouse mast cells saturated with monoclonal mouse IgE anti-DNP antibody. It was found that a 1-min incubation of the sensitized cells with 0.01 micrograms/ml DNP-HSA in the absence of Ca2+ was sufficient to desensitize the cells completely. The treated cells failed to release a detectable amount of histamine upon incubation with an optimal concentration (0.1 to 1.0 micrograms/ml) of DNP-HSA and Ca2+. Determination of the number of antigen molecules bound to mast cells revealed that only a small (less than 10%) fraction of cell-bound IgE antibody molecules reacted with desensitizing antigen, and that desensitized cells and untreated (sensitized) cells could bind comparable amounts of antigen upon incubation with rechallenging antigen. However, the binding of antigen molecules to desensitized cells failed to induce any of the early biochemical events, i.e., phospholipid methylation, cAMP rise, and 45Ca uptake, as well as histamine release. It was also found that intracellular cAMP levels in desensitized cells were comparable to those in sensitized cells. Desensitization by a suboptimal concentration of DNP-HSA was prevented by inhibitors of methyltransferases, such as 3-deaza adenosine plus L-homocysteine thiolactone. Sensitized cells pretreated with 0.01 micrograms/ml DNP-HSA in the absence of Ca2+ and in the presence of the methyltransferase inhibitors responded to an optimal concentration of antigen for histamine release when they were rechallenged in the presence of Ca2+. Inhibition of desensitization by methyltransferase inhibitors was reversed by the addition of S-adenosyl-L-methionine to the system. The results indicated that the activation of methyltransferases, induced by receptor bridging, is involved in the process of desensitization. Desensitization was inhibited by reversible inhibitors of serine proteases, such as p-aminobenzamidine, indole, and synthesized substrates of rat mast cell proteases. It was also found that diisopropylfluorophosphate (DFP), an irreversible inhibitor of serine proteases, completely blocked desensitization at the concentration of 10 to 40 nM. This concentration of DFP did not affect the antigen-induced histamine release, whereas 100- to 1000-fold higher concentrations of DFP did inhibit histamine release. The results suggest that serine proteases are involved in both the induction of histamine release and desensitization, and that the protease involved in desensitization is distinct from that involved in triggering histamine release.
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PMID:Biochemical analysis of desensitization of mouse mast cells. 258 46

The bronchodilating effect and other related pharmacological properties of an 8-amino alkyl substituted xanthine (S 9795) were compared with those of reference drugs, in particular theophylline. The in vitro studies using the tracheal ring, taenia coli, rat peritoneal mastocytes and enzymic preparations demonstrated the potency of S 9795 as an antiasthmatic drug, possessing protective activity superior to that of theophylline and enprofylline. S 9797 was 100 times more active as a cAMP phosphodiesterase inhibitor than theophylline. The compound also protected against mast cell degranulation and consequent release of spasmogen due to antigen-antibody reaction or induced by Ca2+ movements. Given orally or intravenously. S 9795 had a highly selective protective effect against bronchoconstriction induced by pharmacological reagents or allergic reactions with no demonstrable effect on the central nervous or cardiovascular systems. The pharmacological effects of S 9795 were of longer duration than those of theophylline and enprofylline. These studies demonstrate the potential therapeutic value of S 9795 in the therapy of bronchospastic disorders.
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PMID:Pharmacological properties of a new antiasthmatic xanthine derivative devoid of central stimulatory activity. 283 53

In previous studies we showed that rats sensitized to egg albumin respond to in vivo intraluminal antigen with decreased net absorption of Na+, Cl-, and water. These abnormalities are associated with high serum levels of immunoglobulin E (IgE) antibodies and mucosal mast cell degranulation. In the present in vitro study electrical parameters, unidirectional fluxes of Na+ and Cl-, and levels of cAMP were determined in jejunum from sensitized and control rats during a basal period and after antigen addition. In Ussing chambers potential difference and short-circuit current increased significantly in tissue from sensitized rats after addition of 100 micrograms/ml of egg albumin to both mucosal and serosal surfaces. These changes were accompanied by a reversal of net Cl- absorption to net Cl- secretion. The presence of doxantrazole, a mast cell-stabilizing agent, in the buffer prevented these abnormalities. No changes occurred in response to antigen challenge in tissue from controls. In a further series of experiments the antigen was added only to the mucosal side of the tissue in Ussing chambers. In these studies short-circuit current increased after a lag period of approximately 25 min and was significantly increased (P less than 0.025) at 35 min. cAMP levels increased significantly in jejunal slices from sensitized rats exposed to antigen for 2 min. Our findings suggest that the in vivo transport abnormalities induced by IgE-mediated mucosal reactions to a food protein are related to antigen stimulation of a Cl- secretory process.
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PMID:Intestinal anaphylaxis in the rat: jejunal response to in vitro antigen exposure. 300 74

Aminophylline-treated mouse bone marrow-derived mast cells exhibit a hyperresponsiveness to adenosine addition (10(-6) to 10(-4) mol/L) at the time of secretagogue challenge coincident with an up regulation of adenosine receptor numbers. This effect on beta-hexosaminidase release is maximal at 100 mumol/L of aminophylline, evident after 5 days of aminophylline exposure, and reversed by 6 days after washing. Neither radiolabeled arachidonic acid nor leukotriene C4 release in the absence or presence of adenosine was altered by aminophylline treatment. Although cAMP levels were dynamically changed by adenosine or secretagogue, these changes were not different in the two cell populations; resting and challenged mast cell adenosine levels were similarly unaffected by aminophylline. The long-term action of aminophylline on mouse bone marrow-derived mast cells appears to be primarily on adenosine receptors and thereby on preformed mediators, and this action may have some importance in the pathophysiology and treatment of asthma.
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PMID:Aminophylline exposure alters mouse bone marrow-derived mast cell adenosine responsiveness. 302 Jan 10

A new model system for studying biochemical reactions in mast cell plasma membranes was developed. Particles termed cytoplasts consisting of organelle-depleted cytoplasm surrounded by an intact plasma membrane were formed from cytochalasin B-treated mast cells ultracentrifuged through a discontinuous Ficoll gradient. Two cytoplasts were formed per mast cell and 95% were recovered. Mast cell cytoplasts had a mean diameter of 3.2 microns with a median volume of 38 microns 3. Enzyme marker studies indicated that subcellular recoveries in the mast cell cytoplast were: plasma membrane = 16%, cytoplasm = 39%, nucleus = 1.1%, granule = 0.5%. Analysis of IgE receptors indicated that mast cell cytoplasts retained the normal asymmetric orientation of the plasma membrane. Mast cell cytoplasts synthesized ATP, incorporated labeled fatty acids into complex lipids and retained fluorescein after deacylation of diacetylfluorescein. The quantity of cAMP (adenosine 3':5'-cyclic monophosphate) maintained in mast cell cytoplasts was 0.0304 pmol/10(6) original mast cells. Cytoplasts offer the opportunity to study plasma membrane and cytoplasmic biochemical events that occur during stimulation in a relatively physiologic environment.
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PMID:Preparation and characterization of mast cell cytoplasts. 302 28

Activation of white cells, including the neutrophil, eosinophil, basophil, and mast cell, has long been known to be suppressed by high, nonphysiological levels of E-prostaglandins (PGE). In contrast, PGE at levels consistent with an interaction with the PGE receptor (5 X 10(-9) M) have recently been shown to suppress leukotriene (LT) and prostaglandin (PG) production by neutrophils and eosinophils. This occurs by cyclic AMP-dependent inhibition of release of substrate arachidonic acid (AA) from phospholipid pools. The additional observation that indomethacin (10(-9) M) enhances release of eicosanoids by suppressing endogenous PGE2 acting to increase cAMP levels in these cells. Theophylline and other phosphodiesterase inhibitors precisely duplicate the action of PGE2, and the combined effects of such phosphodiesterase inhibitors and adenylate cyclase stimulators are synergistic. The mechanism of action of theophylline in asthma is not know, although it is generally agreed that its effect is a direct one on the bronchial smooth muscle. The findings described in this report now permit the bronchial smooth muscle, but is primarily one of suppressing mediator release from relevant white cells by inhibition of cAMP phosphodiesterase, an action that is enhanced by the presence of inflammatory prostaglandins in the lung.
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PMID:Cyclic AMP-dependent regulation of lipid mediators in white cells. A unifying concept for explaining the efficacy of theophylline in asthma. 303 56

Secretory events in cells in general are accompanied by increased levels of cyclic AMP. In mast cells, however, the pattern is reversed. Thus histamine release is associated with a fall in cAMP. It has been suggested that the lowered levels of cAMP lead to an increase in membrane permeability towards calcium and that an influx of such ions triggers the release mechanisms. It has further been reported that high levels of cAMP inhibit histamine release by decreasing the permeability. However, evidence has now accumulated indicating that this general concept is far too simplistic. Studies are reviewed which imply that there is little or no correlation between histamine release and intracellular levels of cyclic nucleotides. A new working hypothesis with respect to the role of these nucleotides in mast cell secretion is proposed.
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PMID:Cyclic nucleotide involvement in histamine release from mast cells--a reevaluation. 617 75

Theophylline (2.5 mM) did not influence the spontaneous release of histamine but inhibited histamine release induced by antigen, compound 48/80 or phosphatidylserine. The effect on 48/80-induced histamine release could not be reversed by increasing extracellular Ca2+. Exogenous adenosine (10(-8) to 10(-4) M) did not influence spontaneous histamine release or 48/80-induced release but potentiated antigen-induced release. The adenosine potentiation was competitively inhibited by theophylline in concentrations (10(-5) to 10(-4) M) lower than those required to inhibit antigen-induced histamine release in the absence of adenosine. In order to see if endogenous adenosine levels are high enough to potentiate an anaphylactic histamine release in vivo, adenosine was determined in mast cell incubates and in plasma from 4 different strains of rat. The levels were 0.18 to 0.99 microM in plasma, which is sufficient to cause significant potentiation of histamine release, but only 3 x 10(-8) M in mast cell incubates. Theophylline (2.5 mM) increased cAMP levels about 100%, whereas adenosine (10(-5) M) had little effect on cAMP and cGMP levels. However, when incubated together, adenosine could inhibit the theophylline-induced increase in cAMP levels but not the inhibition of histamine release. It is concluded that the effect of low concentrations of theophylline could be due partly to antagonism of adenosine effects. In addition, in higher doses, theophylline appears to exert an inhibitory action that is unrelated to cyclic nucleotides, extracellular calcium and adenosine.
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PMID:On the mechanism by which theophylline inhibits histamine release from rat mast cells. 618 49

The specific activities of pyruvate kinase and phosphofructokinase but not lactate dehydrogenase increase as P-815 mastocytoma cells approach the stationary phase. During this growth period, the rates of uptake of labelled precursors into DNA, RNA and total protein decreases. On the other hand, the pyruvate kinase protein level changes in parallel with activity. Although the K-isozyme is the primary form of pyruvate kinase expressed, some M-type subunit is also present and both forms undergo an increase in specific activity. In addition, pyruvate kinase expression is also elevated by adding cAMP analogues with theophylline, butyrate or conditioned media. This increased level of expression is hypothesized to be a secondary event associated with a differentiation-like-induced expression of the mast cell phenotype.
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PMID:Regulation of pyruvate kinase expression and growth in mastocytoma cells. I. Initial observations. 619 20

A study of the circadian rhythm of cAMP is carried out in ten patients suffering from mixed bronchial asthma, with a marked bacterial component and with sensitizations due to pneumo-allergens (house dust and Dermatophagoides). Cyclic AMP levels were determined before and after treatment with Ketotifen (HC-20511). At the same time, cAMP levels were determined in a control group of 10 healthy subjects in order to realize a comparative study with the asthmatic group. Blood was drawn beginning at 5 AM. at four hour intervals for 24 hours. During this period, medication was withdrawn from these patients, although in some cases antibiotics and mucolytics were administered later; these same patients were treated with Ketotifen in a dose of 1 mg every 12 hours for 5 days. In the blood samples, cAMP levels were determined through a method based on Gilman's technique (comparative protein binding) using the Cyclic AMP Assay Kit (The Radiochemical Center, England). Among the results obtained, there is a clear elevation of cAMP levels in all the determinations after the administration of Ketotifen, maintaining the circadian rhythm with a maximum peak in cAMP levels 5 hours after the drug was given. Thus an increase in all values when compared with basal levels were found arguing in favour of a protective action of this substance carried out through stabilization of the mast cell membrane and thus impeding the release of histamine.
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PMID:A study of the circadian rhythm in 3, 5 cAMP in bronchial asthma after administration of ketotifen. 629 26


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