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Query: UNIPROT:P15088 (mast cell)
14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present investigation was designed to study the histamine release and pharmacologic characteristics of dispersed human lung mast cells, particularly in comparison with parenchymal tissue fragments. Dispersed human lung mast cells were prepared by enzymatic treatment (yield, 0.5 to 2 x 10(6) mast cells/g tissue). Purity was 1 to 8% (mean, 3.6% +/- 0.7%), and histamine content varied from 2 to 6 pg/cell (mean, 3.6 +/- 0.5 pg/cell). Release, studied using anti-IgE as the stimulus, was relatively rapid, being essentially complete within 15 min when high concentrations of anti-IgE (greater than or equal to 0.3 microgram/ml) were used and was not enhanced by phosphatidyl serine. The concentration of drug required to inhibit histamine release by 50% in dispersed cells for a series of pharmacologic agents, including the beta-adrenergic agent fenoterol, the prostaglandin E2, and the phosphodiesterase inhibitor isobutylmethylxanthine, were 0.1 to 1 microM, 50 microM, and 0.5 mM, respectively; similar results were obtained in simultaneous experiments performed using tissue fragments. Adenosine enhanced release (19 +/- 3.4%) at low concentrations (10 microM) and inhibited release (61 +/- 5.1%) at high concentrations (1mM). The H2 agonist, dimaprit (at 10(-5) to 10(-7) M) and prostaglandin D2 (at 10(-4) to 10(-6) M) had no effect on histamine release, whereas deuterium oxide potentiated histamine release. This study serves to quantitate the pharmacologic effects of several agents on anti-IgE-mediated histamine release from dispersed human lung mast cells and has further suggested that the dispersed cell system is similar to the standard chopped lung system in dose-response relationships, kinetics, and pharmacologic modulation. It also indicates that the enzymatic treatment of the cells does not affect the release characteristics or functional capacity of several different receptors, and that this preparation, therefore, appears suitable as an in vitro human model of mediator release that can be used for the evaluation of pharmacologic agents and for further mast cell purification.
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PMID:Dispersed human lung mast cells. Pharmacologic aspects and comparison with human lung tissue fragments. 618 23

The purine nucleosides adenosine and 2',5'-dideoxyadenosine (2',5'ddAdo) enhance and inhibit respectively the anti-IgE-induced secretion of histamine and transient rise in cellular levels of cyclic AMP in rat mast cells. These findings have provided evidence for a role for cyclic AMP in the activation of mast cell secretion. It has been generally accepted that the nucleosides mediate their effects on mast cells by altering adenylate cyclase activity. We have investigated the effect of various purine and ribose modified analogues of adenosine on secretion of histamine from rat mast cells induced by ionophore A23187 for which there is no associated elevation in cyclic AMP and no evidence for the activation of adenylate cyclase in its mechanism of action. Adenosine and N6, phenylisopropyladenosine (0.01-1000 microM) (activators of adenylate cyclase in many tissues) enhanced the secretion of histamine induced by ionophore A23187 and anti-IgE. Two inhibitors of adenylate cyclase had differential effects on secretion. 2',5'ddAdo (100-1000 microM) inhibited both A23187-and anti-IgE-mediated secretion; whilst 9-beta-D-arabinofuranosyladenine had no effect on secretion. These results suggest that the ability of these nucleosides to modulate histamine secretion is unrelated to their effects on adenylate cyclase.
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PMID:The effect of ribose and purine modified adenosine analogues on the secretion of histamine from rat mast cells induced by ionophore A23187. 619 99

Adenosine, at physiological concentrations, may modulate histamine release from mechanically dispersed human lung mast cells. Addition of adenosine to the dispersed mast cells at times up to 5 min before immunological challenge with anti-human IgE inhibited histamine release. When added after this time adenosine caused a small potentiation of immunological histamine release, maximum potentiation occurring with addition of adenosine 5 min after challenge, coincidental with the end of the rapid phase of histamine release. Both inhibition and potentiation of histamine release were more pronounced with low levels of immunological challenge. Theophylline, 8-phenyltheophylline, dipyridamole and analogues of adenosine were used to determine the site of action of adenosine on mast cell mediator release. Theophylline and 8-phenyltheophylline displaced the concentration-response lines for both inhibition and potentiation of mediator release by adenosine to the right whilst dipyridamole, 1 microM, was without significant effect. This suggests that both effects result from interaction of adenosine with cell surface receptors. This was confirmed by demonstrating that the P-site agonist 2',5'-dideoxyadenosine produced only inhibition of histamine release, an effect which was inhibited by dipyridamole but not by theophylline. The rank potency order of adenosine analogues, NECA much greater than adenosine greater than or equal to L-PIA greater than or equal to D-PIA in both inhibiting and potentiating immunological histamine release suggests that both effects are mediated through activation of cell surface A2-purinoceptors. Since adenosine is released into the circulation of asthmatic subjects following bronchial provocation with antigen, causes bronchoconstriction and has the ability to modulate mast cell histamine release, this nucleoside should be considered as an additional inflammatory mediator of allergic reactions.
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PMID:Adenosine inhibits and potentiates IgE-dependent histamine release from human lung mast cells by an A2-purinoceptor mediated mechanism. 621 89

Adenosine receptors on mouse bone marrow-derived mast cells were identified by functional criteria and radioligand binding. The stimulated release of beta-hexosaminidase from these cells was significantly augmented by the simultaneous addition of secretagogue and adenosine, NECA, or L-PIA. Similar enhancement of pre-formed mediator release occurred after a 10-min preincubation with adenosine. Resting mast cell cAMP levels increased within 15 sec after the addition of adenosine, and remained elevated for at least 60 sec. Although the antigen-or A23187-induced release of beta-hexosaminidase was markedly potentiated by exogenous adenosine, the stimulated release of [14C]-labeled arachidonic acid metabolites was minimally affected by adenosine, suggesting a differential effect of adenosine on granule-associated release as compared to generated mediator release. Bone marrow mast cells exhibited 5470 +/- 740 [3H]adenosine binding sites/cell, with a binding affinity of 24.4 +/- 3.8 nM. Cells cultured in the presence of 100 microM aminophylline for 6 days were hyperresponsive to exogenous adenosine, releasing a maximum of 162% of the amount of beta-hexosaminidase released from control cells in the presence of adenosine. The number of [3H]adenosine binding sites on the xanthine-treated cells increased to 156% of control values, suggesting an up-regulation of adenosine receptors induced by chronic exposure to an adenosine receptor antagonist. Mouse bone marrow mast cells possess functionally significant adenosine receptors that are regulated by aminophylline and that, when stimulated, produce many alterations in the mast cell secretory process.
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PMID:Adenosine receptors on mouse bone marrow-derived mast cells: functional significance and regulation by aminophylline. 633 Feb 5

Adenosine potentiates mast cell activation, but the receptor type and molecular mechanisms involved have not been defined. We, therefore, investigated the effects of adenosine on the human mast cell line HMC-1. Both the A2a selective agonist CGS21680 and the A2a/A2b nonselective agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased cAMP, but NECA was fourfold more efficacious and had a Hill coefficient of 0.55, suggesting the presence of both A2a and A2b receptors. NECA 10 microM evoked IL-8 release from HMC-1, but CGS21680 10 microM had no effect. In separate studies we found that enprofylline, an antiasthmatic previously thought to lack adenosine antagonistic properties, is as effective as theophylline as an antagonist of A2b receptors at concentrations achieved clinically. Both theophylline and enprofylline 300 micro completely blocked the release of IL-8 by NECA. NECA, but not CGS21680, increases inositol phosphate formation and intracellular calcium mobilization through a cholera and pertussis toxin-insensitive mechanism. In conclusion, both A2a and A2b receptors are present in HMC-1 cells and are coupled to adenylate cyclase. In addition, A2b receptors are coupled to phospholipase C and evoke IL-8 release. This effect is blocked by theophylline and enprofylline, raising the possibility that this mechanism contributes to their antiasthmatic effects.
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PMID:Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. 756 91

Adenosine activates adenylate cyclase and phospholipase C in mast cells and potentiates stimulated mediator release. To determine whether activation of adenylate cyclase is necessary for the effects of adenosine on the mast cell secretory process, a specific inhibitor of cAMP-dependent protein kinase, KT5720, was used. Antigen and adenosine each induced a rapid increase in mast cell cAMP-dependent protein kinase activity within 30 s. Preincubation with KT5720 (100 nM-10 microM) suppressed cAMP-dependent protein kinase activity and inhibited antigen-stimulated beta-hexosaminidase and leukotriene C4 releases. Adenosine retained its ability to potentiate beta-hexosaminidase release in antigen- and A23187-stimulated cells even in the presence of complete cAMP-dependent protein kinase inhibition. Mast cells rendered unresponsive to adenosine-related signals by preincubation with adenosine analogs maintained this hyporesponsiveness after incubation with KT5720. It appears that the abilities of adenosine to augment mast cell degranulation and induce receptor hyporesponsiveness are independent of changes in cAMP.
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PMID:Inhibition of protein kinase A fails to alter mast cell adenosine responsiveness. 774 Oct 46

Adenosine potentiates the stimulated release of mast cell mediators. Pharmacologic studies suggest the presence of two adenosine receptors, one positively coupled to adenylate cyclase and the other coupled to phospholipase C activation. To identify mast cell adenosine receptor subtypes, cDNAs for the A1 and A2a adenosine receptors were obtained by screening a mouse brain cDNA library with the use of PCR-derived probes. Mouse bone marrow-derived mast cell cDNA libraries were constructed and screened with the use of A1 and A2a cDNA probes, which revealed the presence of A2a, but not A1, receptor clones. A putative A2b receptor was identified by using low stringency mast cell library screening. Northern blotting of mast cell poly(A)+ RNA with the use of receptor subtype probes labeled single mRNA bands of 2.4 kb and 1.8 kb for the A2a and A2b receptors, respectively. In situ cells. An A2a receptor-specific agonist failed to enhance mast cell mediator release, which suggests that the secretory process is modulated through the A2b and/or another receptor subtype. By using RNase protection assays, we found that mast cells that had been cultured in the presence of N-ethylcarboxamidoadenosine for 24 h exhibited a decrease in both A2a and A2b receptor RNA levels. Cells that had been cultured for 1 to 2 days in the presence of dexamethasone demonstrated increased amounts of A2a receptor mRNA, but no identifiable change in A2b receptor mRNA. Mast cells possess at least two adenosine receptor subtypes that may be differentially regulated.
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PMID:Cloning of two adenosine receptor subtypes from mouse bone marrow-derived mast cells. 815 66

Adenosine (Ado) is a potent vasodilator that has occasionally been shown to cause vasoconstriction. Constrictor responses are generally attributed to A1-receptor stimulation or interactions with the renin-angiotensin system. We describe a previously unreported vasoconstrictor action of Ado and inosine (Ino) in hamster cheek pouch arterioles and examine the mechanism by which these nucleosides induce constriction. Arterioles were dissected from male Golden hamster cheek pouches, transferred to a 37 degrees C tissue chamber, and cannulated at both ends. Changes of luminal diameter in response to Ado were measured to generate cumulative concentration-response curves. The concentration-response curves were biphasic: 10(-6) M Ado elicited an intense, transient constriction, and higher concentrations induced dilator responses. Pretreatment with 8(p-sulfophenyl)theophylline, an Ado receptor antagonist, inhibited the dilator responses but did not alter the constriction. Inhibition of Ado uptake with S-(4-nitrobenzyl)-6-thio-inosine eliminated the constrictor response without altering dilator responses. Similar effects were found after pretreatment with an Ado deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride. Finally, Ino, a metabolite of Ado, induced constrictions of similar magnitude to those seen with Ado, but at higher concentrations. The constrictor response was focal in nature, suggesting discrete sites of action of Ado. Methylene blue staining after Ado application revealed degranulated mast cells closely associated with the vessel wall, indicating a possible role for mast cell degranulation in the constrictor response. Supporting this idea were the observations that inhibition of degranulation by 10 microM cromolyn blocked the constrictor response, and compound 48/80 (a mast cell secretagogue) caused constriction similar to that elicited by Ado.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nucleoside-induced arteriolar constriction: a mast cell-dependent response. 820 2

Mast cells release the mediators of the immediate hypersensitivity reaction. Adenosine is known to modulate this process, but the receptor responsible for this is not the classical A1 or A2 adenosine receptors. This study was undertaken to determine whether the unique adenosine receptor (AR) previously postulated in a cultured mast cell line (RBL-2H3 cells) is the recently cloned A3AR. The receptors were quantitated by the agonist 125I-labeled APNEA (aminophenylethyladenosine), an A3AR agonist, which yielded Bmax and Kd values of 826 fmol/mg protein and 34 nM, respectively. A variety of adenosine analogs competed for 125I-APNEA binding sites with the following potency series: (R)-phenylisopropyladenosine = 5'-N-ethylcarboxamide adenosine > (S)-phenylisopropyladenosine. 125I-APNEA binding was relatively insensitive to the xanthine amine congener (XAC, 1 microM), a selective antagonist for the A1AR. Functionally, activation of these A3AR stimulated the production of inositol 1,4,5-triphosphate, leading to an increase in the level of intracellular Ca2+. Furthermore, while activation of these receptors alone produced little secretory response in RBL-2H3 cells, it enhanced antigen-induced secretion by 2-2.5-fold. Northern blotting studies using poly(A+) RNA from RBL-2H3 cells detected two transcripts of 2.0 and 3.5 kilobases, which hybridized to an A3AR cDNA but not to the A1 or A2AR cDNA probes. These data indicate that the unique AR that potentiates the secretory response to antigen in RBL-2H3 cells is exclusively the A3AR.
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PMID:The A3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. 834 79

The inhalation of adenosine or adenosine-5'-monophosphate (AMP) causes a reproducible and transient bronchoconstriction in both atopic and nonatopic asthmatic subjects that is not followed by a late-phase response. The response may be prevented by prophylactic treatment with histamine H1-receptor antagonist, local anesthetics, and atropine, which suggests that both mast cell mediator release and neuronal reflexes are involved. Adenosine- and AMP-induced bronchoconstriction are both blocked by cromolyn sodium and nedocromil sodium, with the PD20FEV1 for the latter approximately four times lower than that of cromolyn sodium in atopic asthmatic patients and approximately 2.3 times lower than that of cromolyn sodium in nonatopic asthmatic patients. We suggest that AMP-induced bronchoconstriction, in combination with other indirect-acting provicants, may be used to determine the effectiveness and mechanism of action of antiasthmatic drugs.
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PMID:Adenosine-induced bronchoconstriction and its inhibition by nedocromil sodium. 839 27


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