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)

Adenosine was found to modulate the activity of the human basophil and lung mast cell (HLMC) differently. In the basophil, adenosine inhibited the anti-IgE stimulated release of histamine and leukotriene C4 (LTC4) and increased total cell cyclic AMP (cAMP) levels. Substituted adenosine analogs had a rank order potency of: N-ethylcarboxamideadenosine (NECA) greater than 2-chloroadenosine greater than R-phenylisopropyladenosine for the inhibition of immunoglobulin E-triggered mediator release from the basophil and increases in cAMP levels. The adenosine receptor antagonist, 8-phenyltheophylline, antagonized both the NECA-induced inhibition of mediator release and elevations in cyclic nucleotide. The purinergic transport inhibitor, dipyridamole, reversed the inhibition by adenosine of histamine release but not LTC4 generation, suggesting that these two actions are mechanistically separable. Dipyridamole failed to modify the adenosine-induced elevation in cAMP. In contrast to the findings in the basophil, the response to adenosine in the HLMC was biphasic in nature. Thus, at low concentrations of the nucleoside, adenosine potentiated the release of histamine and LTC4 from immunologically activated HLMC, whereas at higher concentrations a counteractive inhibitory process was observed. Analogs of adenosine had the same effects on HLMC; NECA was more potent than R-phenylisopropyladenosine for both the potentiating and inhibitory components of the biphasic response. Low concentrations of adenosine analogs, which potentiated secretion, initiated modest elevations in cAMP levels, whereas higher concentrations, which inhibited secretion, significantly augmented cAMP levels. Although R-phenylisopropyladenosine was almost as potent as NECA at elevating cAMP in HLMC, it was not as efficacious. The NECA-induced modulation of HLMC mediator release and elevations in cAMP were antagonized by 8-phenyltheophylline.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential regulation of human basophil and lung mast cell function by adenosine. 170 36

1. Inhaled adenosine and its parent nucleotide, adenosine 5'-monophosphate (AMP) provoke bronchoconstriction in atopic and asthmatic individuals but not in normal subjects. 2. In clinical studies, histamine H1-receptor antagonists, cyclo-oxygenase inhibitors and the mast cell 'stabilising' drugs, sodium cromoglycate and nedocromil, protect against the effects of adenosine bronchoprovocation suggesting the involvement of secondary mast cell mediator release. 3. Adenosine and its analogues potentiate histamine and leukotriene release from mast cells activated by other stimuli in vitro, and may also increase net mediator release from mast cells by counteracting the inhibitory effect of circulating adrenaline. 4. Although adenosine fulfils many of the criteria required for a mediator in asthma, its importance is not fully understood, and the mechanisms by which it provokes bronchoconstriction in asthmatic subjects is far from concluded. 5. Two possibilities are that either adenosine acts directly on luminal mast cells to upregulate histamine secretion, or it acts to initiate neuronal reflexes which stimulate histamine release indirectly and possibly activate peptidergic and/or cholinergic pathways.
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PMID:Adenosine bronchoconstriction in asthma: investigations into its possible mechanism of action. 226 11

Mast cells from adenoid tissues of man do not form a homogeneous population but differ in size and ultrastructure. They degranulate on stimulation with specific antigen, ionophore A 23187, Concanavalin A and, under certain conditions, antihuman IgE or acetylcholine. Compound 48/80, dextran, purified C3a or C5a are ineffective. Adenosine exerts either an enhancing or inhibiting effect on the stimulated histamine release, depending on the actual conditions of the mast cells. The study of a range of known mast cell degranulation inhibitors revealed important differences between human adenoidal mast cells and human basophils or animal mast cell systems. The efficacies of the drugs or drug combinations so far tested correspond well with the established therapeutic effects in man.
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PMID:The human adenoidal mast cell. Susceptibility to different secretagogues and secretion inhibitors. 240 16

The effects of adenosine and its analogues on cAMP-responses and histamine release of rat peritoneal mast cells were investigated. The adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA') activates the adenylate cyclase of the mast cell membranes and elevates the cAMP-levels of the intact mast cells. Both effects are antagonized by methylxanthines, suggesting that they are mediated via an A2 adenosine receptor. Adenosine and its analogues enhance the release of histamine from these cells, when the release is stimulated either by the calcium ionophore A 23187 or by concanavalin A. However, this effect is not antagonized by theophylline or 8-phenyltheophylline. In contrast, it is antagonized by the adenosine uptake blockers S-(p-nitrobenzyl)-6-thioinosine (NBTI) and S-(p-nitrobenzyl)-6-thioguanosine (NBTG). It is concluded that adenosine has two different effects on mast cells: it activates adenylate cyclase via an A2 adenosine receptor, and it enhances histamine release via an action at an intracellular site.
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PMID:Dual actions of adenosine on rat peritoneal mast cells. 244 Dec 69

Adenosine, which may be formed by all cells during relative energy or oxygen deficit, may act as an autocoid by modifying the function of other cells in the local environment. In asthmatic, but not normal, subjects, inhalation of adenosine causes a marked bronchoconstriction which may be reduced by the purinoceptor antagonist theophylline, sodium cromoglycate, nedocromil sodium, histamine, H1-antagonists and cyclo-oxygenase inhibitors. Repeated exposure to adenosine induces a state of tachyphylaxis and cross-tachyphylaxis with exercise-induced bronchoconstriction but not with that provoked by allergen. Although the mechanisms by which adenosine induces changes in airways function are not clear, it is suggested that it has an indirect effect, possibly by up-regulating bronchoconstrictor factors already present in asthma such as mast cell mediator release or neuronal reflexes.
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PMID:Adenosine as a pro-inflammatory mediator in asthma. 252 Apr 85

Adenosine potentiates preformed mediator release from mouse bone marrow-derived mast cells stimulated with specific Ag or the calcium ionophore A23187. When these mast cells were cultured for 30 to 120 min with the phorbol ester PMA (10(-8) or 10(-7) M), protein kinase C activity was increased and Ag-stimulated beta-hexosaminidase release was modestly inhibited, whereas A23187-stimulated release was synergistically enhanced. However, in both cases, exogenous adenosine failed to augment beta-hexosaminidase release. Overnight PMA exposure produced a decrease in protein kinase C activity and a decrease in both Ag- and A23187-stimulated preformed mediator release, as well as a lack of responsiveness to adenosine. This hyporesponsiveness could be reversed by 24 h after washing the cells free of PMA. The generation of the arachidonic acid metabolite leukotriene C4 was not altered by mast cell PMA exposure. The ability of adenosine to increase intracellular cAMP concentrations was modestly blunted by high doses of PMA, and PMA abrogated the increase in intracellular free calcium levels usually observed in cells stimulated with Ag in the presence of 10(-5) M adenosine. PMA exposure induces a hyporesponsiveness to adenosine in mast cells, either by a direct effect on protein kinase C activity and/or by an effect on adenosine receptor expression or recycling.
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PMID:Pretreatment with phorbol esters abrogates mast cell adenosine responsiveness. 253 70

Adenosine potentiates mouse bone marrow-derived mast cell mediator release by a mechanism that appears to involve cell surface adenosine receptors. In an attempt to explore possible interactions between G proteins and adenosine receptors, mast cells were incubated with activated pertussis toxin, an agent that ADP-ribosylates and inactivates some G protein subtypes, prior to challenge with specific antigen or the calcium ionophore A23187. Mast cells preincubated with 10 ng/ml pertussis toxin for at least 2 hr exhibited an inhibition of antigen-induced beta-hexosaminidase and leukotriene C4 release. The ability of adenosine to potentiate beta-hexosaminidase release was attenuated to an even greater degree by pertussis toxin. A23187-stimulated mediator release was not altered by pertussis toxin, although a modest inhibition of the ability of adenosine to enhance A23187-induced beta-hexosaminidase release was observed in pertussis toxin-treated mast cells. Although up to 24-hr exposure to 100 ng/ml pertussis toxin did not alter resting mast cell cyclic AMP levels, the ability of adenosine to elevate cell cyclic AMP concentrations was diminished markedly by doses of the toxin higher than those required to affect mediator release. Neither antigen-stimulated intracellular free calcium level augmentation alone nor the additional potentiation of these levels by adenosine was changed by pertussis toxin treatment. Inositol trisphosphate was generated by mast cells stimulated by IgE-mediated mechanisms, but a preincubation with pertussis toxin did not influence its generation. In summary, adenosine appeared to produce some of its alterations in mast cell biochemical events by a mechanism that was partially inhibited by pertussis toxin. The nature of the G protein linked to the mast cell adenosine receptor is yet to be determined.
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PMID:Alteration of mast cell responsiveness to adenosine by pertussis toxin. 284 50

Adenosine, when it is administered by inhalation to asthmatic subjects, is a potent bronchoconstrictor, although its mechanism of action is not known. Since adenosine has been demonstrated to potentiate IgE-dependent mediator release from mast cells, we have investigated the possible relationship between adenosine-induced bronchoconstriction and release of mast cell mediators in 14 asthmatic subjects. In the first study the effect of the putative mast cell-stabilizing drug cromolyn sodium (SCG) was observed on the dose-related changes in SGaw and FEV1 produced by inhaled adenosine and histamine in seven subjects. Inhaled SCG (20 mg) had no effect on the airway responses to histamine. In contrast SCG significantly protected against adenosine-induced bronchoconstriction in four of the seven subjects as reflected by a decrease in the airway response to the highest concentrations of adenosine, from 65 +/- 8% to 12 +/- 3% (mean +/- SEM) for SGaw and 31 +/- 7% to 8 +/- 3% for FEV1. Those three subjects whose adenosine response was unaffected by SCG had received regular SCG until 12 hr before the studies. In a separate study on eight subjects, a single inhalation of adenosine, causing a maximum 61 +/- 4% fall in SGaw at 10 min, had no significant effect on circulating levels of histamine, neutrophil chemotactic factor, or cyclic AMP. Together these two studies suggest that bronchoconstriction produced by adenosine is not a consequence of enhanced mast cell-mediator release and that the inhibitory effects of SCG occur by a mechanism other than through mast cell stabilization.
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PMID:Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release. 298 12

Rat serosal mast cell adenosine receptors were characterized by [3H]adenosine binding to cell membrane particulates, and functional changes in mast cell mediator release and cyclic AMP levels were assessed, utilizing various adenosine analogs. [3H]adenosine binding to sonicated mast cell membrane preparations at 0 degrees C in the presence of deoxycoformycin is linear with initial cell number, rapid and reversible. The cells display 16,400 +/- 1600 high affinity [3H]adenosine binding sites/cell, equivalent to 118 fmol bound/mg protein, with an equilibrium dissociation constant of 27.97 +/- 3.0 nM. Competition studies reveal that adenosine greater than 2-chloroadenosine greater than NECA greater than L-PIA greater than D-PIA in competing for [3H]adenosine binding sites and that aminophylline and cromolyn sodium also bind to the putative receptor. Adenosine and its analogs, NECA, and L-PIA, appear to activate adenylate cyclase in resting mast cells by raising cyclic AMP, suggesting an Ra cell surface adenosine receptor subtype; these same analogs potentiate mast cell B-hexosaminidase release stimulated by specific antigen. The identification of rat mast cell [3H]adenosine binding sites whose stimulation augments resting cell cyclic AMP levels and antigen-induced mediator release suggests that these receptors may be important in the biochemical mechanisms of allergic diseases. The ability to assess the number and affinity of mast cell adenosine receptors will enable one to monitor receptor alterations during pharmacologic manipulation and in disease states.
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PMID:[3H]Adenosine binding to rat mast cells--pharmacologic and functional characterization. 300 Jan 51

Mast cells are central to the development of bronchial inflammation and thus to bronchial hyperreactivity, the cardinal feature of asthma. Inflammation is due to the concerted action of mast cell-dependent vasoactive/spasmogenic mediators, chemotactic factors, and enzymes. Adenosine, a newly synthesized mast cell mediator (from adenosine triphosphate), is one of the important inflammatory mediators capable of causing bronchospasm and, by interacting with mast cell membrane receptors, of augmenting mediator release induced by antigen. These inflammatory and pro-asthmatic actions of adenosine can be inhibited by concentrations of theophylline achievable in humans that are insufficient to alter cyclic adenosine monophosphate metabolism. Thus, a new therapeutic consideration in the use of xanthine drugs is their ability to inhibit adenosine binding to cell surface receptors and thereby inhibit the effects of this purine nucleoside.
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PMID:The mast cell and theophylline in asthma. 300 76


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