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 have been traditionally associated with an acute allergic response. However, their role in regulating chronic inflammatory processes must also be considered in view of evidence that mast cells synthesize and release a number of cytokines. In this study, we have examined the effect of cholera toxin (CT) on peritoneal mast cell IL-6 and TNF-alpha production. Highly purified, freshly isolated, rat peritoneal mast cells from Brown Norway rats were cultured in the presence of CT or its B subunit (CTB) alone or in combination with anti-IgE or bacterial LPS. Histamine release was measured after 10 min; IL-16 and TNF-alpha production was assessed in supernatants after 18 h. We found that CT or CTB alone did not affect histamine release; however, mast cell IL-6 production was significantly enhanced by CT but not by CTB. In contrast, constitutive production of TNF-alpha was inhibited by CT. The effects of CT were similar to our previous observations of the actions of prostaglandin E2 on mast cells. We also examined the effects of CT in combination with other mast cell activating agents. CT had no significant effect on anti-IgE-induced histamine release. An additive effect on IL-6 production was observed in the context of LPS. Forskolin, an agent known to increase intracellular cAMP levels, also induced a significant increase in IL-6 production, whereas TNF-alpha production was decreased. These data have important implications for our understanding of the regulation of mast cell cytokine production and the effects of CT on local cytokine production.
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PMID:Cholera toxin increases IL-6 synthesis and decreases TNF-alpha production by rat peritoneal mast cells. 859 79

While investigating an involvement of other factors aside from endogenous IL-3 and prostaglandin E (PGE) in mast cell induction from mouse splenocytes, we found that the mast cell induction was inversely proportional to IL-4 levels and tended to directly proportionate IFN-gamma levels in the supernatants recovered on days 2 and 4. Thereafter, we examined the effects of rIFN-gamma, rIL-4, and rIL-10 on mast cell induction. IFN-gamma and IL-10 dose-dependently induced mast cells. Time course study showed an importance of adding rIFN-gamma into the cultures at the early phase (on days 0 and 2 of a 12-day culture). When endogenous IFN-gamma at the early phase was neutralized by anti-IFN-gamma Ab, all stimulants, including rIFN-gamma, rIL-10, and PGE1, failed to induce mast cells. On the contrary, rIL-4 dose-dependently suppressed the mast cell induction by rIFN-gamma, rIL-10, LPS, PGE, and dibutyryl cAMP. The inhibitory effect of IL-4 was observed when IL-4 was added into the cultures at the early phase, but not after day 4. The suppressive action of IL-4 was diminished completely by the addition of neutralizing anti-IL-4 Ab. IL-12, a key regulator of IFN-gamma and IL-4 production, also induced mast cells. These results revealed, for the first time, that IFN-gamma is crucial for the survival and/or differentiation of splenic mast cell precursors and that IL-4 is a key inhibitor for the precursors, although IFN-gamma is not a mast cell growth factor and IL-4 is a growth factor for immature and mature mast cells.
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PMID:Down-regulation by IL-4 and up-regulation by IFN-gamma of mast cell induction from mouse spleen cells. 862 32

Using pharmacologic agents, we explored the mechanism by which a potent neuropeptide, substance P, induces the secretion of histamine from human skin mast cells and compared their effects on substance P-induced histamine release to the secretion activated by anti-IgE. Histamine release from human cutaneous mast cells induced by substance P was inhibited by the Ge-protein inhibitor pertussis toxin that, in turn, did not affect the IgE-mediated secretion. Similarly to anti-IgE, two activators of protein kinase C, tetradecanoylphorbol acetate (TPA) and bryostatin 1, significantly inhibited the substance P-induced response. In contrast, drugs that enhance intracellular levels of cAMP, an inhibitor of protein kinases, genistein, and a protease inhibitor, AEBSF, did not affect substance P-induced histamine secretion, whereas these compounds significantly reduced the response initiated by anti-IgE. Our data demonstrate that substance P activates human cutaneous mast cells by acting on G proteins and protein kinase C. Our results also suggest that the biochemical pathways underlying mast cell activation by substance P and anti-IgE are to a great extent unrelated.
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PMID:Substance P activates the release of histamine from human skin mast cells through a pertussis toxin-sensitive and protein kinase C-dependent mechanism. 880 44

We have previously shown the presence and localization of mast cells and the intraocular effects of compound 48/80 in the rabbit eye. In the present study we have evaluated the mechanism of action of compound 48/80 using ruthenium red as a blocker of sensory axon reflexes in the rabbit eye and by measuring the intraocular pressure (IOP), the pupil size, the blood pressure, the protein and cAMP content in the aqueous humour. Topical neutral formaldehyde was used as a topical inducer of neuronally mediated response in a separate series of experiment. Intracamerally-injected ruthenium red suppressed the compound 48/80-induced elevation intraocular pressure and prevented miosis, while having little if any effect on the breakdown of the blood-aqueous barrier and on the increase in the cAMP concentration in aqueous humour. Ruthenium red also inhibited the irritative response in eyes treated with topical 1% formaldehyde. As the blood-aqueous barrier in the rabbit is an extremely sensitive system higher doses of ruthenium red causes damage of the barrier in the ruthenium red treated eyes. The results demonstrate that compound 48/80 not only has a mast cell degranulating effect but also a sensory nerve- stimulating effect.
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PMID:Intraocular effects of ruthenium red in responses to compound 48/80 and topical formaldehyde in rabbit. 892 1

The effect of an aqueous extract of Poncirus trifoliata (L.) Raf. (Rutaceae) fruits (PTFE) on compound 48/80-induced mortality associated with anaphylaxis was studied in rats. PTFE inhibited compound 48/80-induced anaphylaxis 100% with a dose of 1.6 mg/g body weight (BW) 1 h before or 5 min after injection of compound 48/80. PTFE inhibited compound 48/80-induced anaphylaxis almost 100% with doses above 0.4 mg/g BW intraperitoneally administered. PTFE (1-1000 micrograms/ml) also dose-dependently inhibited the histamine release induced by compound 48/80 (5 micrograms/ml) in rat peritoneal mast cells. The level of cAMP in peritoneal mast cells, when PTFE was added, increased transiently, and significantly increased 53-fold at 10 s compared with that of basal cells. Moreover, PTFE inhibited intracellular calcium release induced by compound 48/80. These results suggest that PTFE has antianaphylactic activity by stabilizing the peritoneal mast cell membrane.
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PMID:Antianaphylactic activity of Poncirus trifoliata fruit extract. 895 21

The inhibitory effect of cromakalim on the mediator release from mast cells caused by antigenantibody reactions was in controversy with the specific antigen used. However, it has recently been observed that cromakalim inhibits the release of mediators from superfused tracheal and parenchymal strips or lung mast cells after passive sensitization with the IgG1 antibody. An attempt, therefore, was made to determine the inhibitory mechanisms of cromakalim on the release of mediators such as histamine and leukotriene released by the activation of enzymes during mast cell activation. Guinea pig lung mast cells were purified through enzyme digestion, rough percoll and continuous percoll density gradients. The purified mast cells were prelabeled with [3H]palmitic acid. PLD activity was assessed more directly by the production of labeled phosphatidylethanol by PLD-mediated transphosphatidylation in the presence of ethanol. In the cells labelled with [3H]myristic acid, [3H] DAG production was measured. The methyltransferase activity was assessed by measuring the incorporation of [3H]methyl moiety into phospholipids in sensitized mast cells labelled with L-[3H] methylmethionine. cAMP level was measured by radioimmunoassay. Cromakalim resulted in a decrease in the amount of histamine and leukotrienes releases by 30% in the ovalumin-induced mast cell. Cromakalim had little effect on phospholipase D activity enhanced by the activated mast cell. Cromakalim inhibited the initial increase of diacylglycerol production during mast cell activations. Cromakalim inhibited the phospholipid methylation increased in the activated mast cell. These results show that cromakalim decreases histamine release by inhibiting the initial increase of 1,2-diacylglycerol during the mast cell activation, which is mediated via the phosphatidylinositide-phospholipase C system rather than the phosphatidylcholine-phospholipase D system. Furthermore, cromakalim reduces phosphatidylcholine production by inhibiting the methyltransferase, which decreases the conversion of phosphatidylcholine into arachidonic acid and inhibits the production of leukotrienes.
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PMID:The effects of cromakalim on the mediator releases from guinea pig lung mast cell activated by specific antigen-antibody reactions. 899 65

In previous articles we have reported the "disappearance" of Harderian gland mast cells (HGMC) after treatment with testosterone. In the present work we study: (a) if the apparent decrease in the number of mast cells caused by this androgen is real or is due to the fact that testosterone induces mast cell degranulation that avoids its recognition by toluidine blue staining; (b) if testosterone acts through its receptor directly on the Harderian gland (HG). In order to give an answer to the first question, we observed HG of female Syrian hamsters treated with testosterone under the electron microscope to find the possible degranulated mast cells not recognizable with the aid of the toluidine blue staining. We also studied in vivo and in vitro the effects of the beta-agonists isoproterenol and salbutamol, given that they increase cAMP and can therefore prevent degranulation of mast cells. Finally we have used cytocalasin B, which inhibits degranulation by blocking actin depolimerization. Both the beta-agonists and cytochalasin B were able to prevent the decrease of mast cells, as recognized by staining with toluidine blue after treatment with testosterone. Indeed, when observed under the electron microscope, abundant degranulated mast cells were found after treatment with testosterone. For solving the second issue we analyzed the effect of the antiandrogen cyproterone acetate in vivo and in vitro. Our results demonstrate that testosterone is able to induce degranulation of HGMC in the Syrian hamster Mesocricetus auratus and that this effect is achieved directly through its receptor on the Harderian gland.
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PMID:Androgen-dependent mast cell degranulation in the Harderian gland of female Syrian hamsters: in vivo and organ culture evidence. 927 58

To study the suitability of the microdialysis technique for the measurement of target tissue pharmacodynamics in humans, the model compounds theophylline, milrinone, and compound 48/80 were administered locally by means of reversed microdialysis to the interstitial space of skeletal muscle or skin in 24 healthy volunteers. Simultaneously, interstitial concentrations of cyclic adenosine monophosphate (cAMP; as an indicator of phosphodiesterase activity) were measured in skeletal muscle, and interstitial concentrations of histamine (as an indicator of mast cell release) were measured in skin. In muscle, reversed microdialysis with milrinone led to a dose-dependent increase in interstitial cAMP concentrations (n = 8), whereas no significant effect on cAMP was observed for theophylline versus placebo (1.63 +/- 0.53 nmol/L; n = 6), even at local concentrations exceeding those attained after therapeutic doses. In skin, reversed microdialysis with compound 48/80 increased interstitial histamine concentration dose dependently versus placebo (5.99 +/- 2.74 nmol/L; n = 10). From our experiments in human skeletal muscle and skin, we concluded that microdialysis was a suitable technique for the characterization of in vivo drug response at the relevant target site. Extension of these measurements to several other human tissues is readily feasible.
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PMID:In vivo drug-response measurements in target tissues by microdialysis. 928 52

We cloned and characterized the canine A3 adenosine receptor (AR) and examined AR-induced degranulation of the BR line of canine mastocytoma cells. Canine A3AR transcript is found predominantly in spleen, lung, liver, and testes and encodes a 314-amino acid heptahelical receptor. 125I-N6-Aminobenzyladenosine binds to two affinity states of canine A3AR with KD values of 0.7 +/- 0.1 and 16 +/- 0.8 nM, reflecting G protein-coupled and -uncoupled receptors, respectively. Xanthine antagonists bind with similar affinities to human, canine, and rabbit receptors but with 80-400-fold lower affinities to rat A3AR. Although canine BR mastocytoma cells contain A1AR, A2BAR, and A3AR, degranulation seems to be mediated primarily by A2BARs stimulated by the nonselective agonist 5'-N-ethylcarboxamidoadenosine (NECA) but not by the A3-selective agonist N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide. NECA-stimulated degranulation is not prevented by pertussis toxin and is blocked by enprofylline (Ki = 7 microM), an antiasthmatic xanthine with low affinity (Ki > 100 microM) for A1AR, A2AAR, and A3AR. NECA increases canine mastocytoma cell cAMP, Ca2+, and inositol trisphosphate levels; these responses are antagonized half-maximally by 7-15 microM enprofylline. The results suggest that (i) the cloned canine A3AR is structurally and pharmacologically more similar to human than to rat A3AR; (ii) the A2BAR, and not the A1AR or A3AR, is principally responsible for adenosine-mediated degranulation of canine BR mastocytoma cells; and (iii) the BR cell A2BAR couples to both Ca2+ mobilization and cAMP accumulation. Although A2B receptors play a major role in the regulation of BR mast cell degranulation, multiple AR subtypes and G proteins may influence mast cell functions.
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PMID:Canine mast cell adenosine receptors: cloning and expression of the A3 receptor and evidence that degranulation is mediated by the A2B receptor. 935 76

Characterization of A2B receptors is hampered by the lack of selective pharmacological probes and often relies on their relative affinity to agonists that are selective at other receptor types. This approach is limited because the affinity of A2B receptors for putative A3 agonists has not been determined. Using the human erythroleukemia cell line HEL as a cellular model for A2B-mediated adenylate cyclase activation, we found the following potencies (pD2) for the non-selective agonist 5'-N-ethylcarboxamidoadenosine (NECA) (5.65 +/- 0.04), the putative A3 agonists N6-benzyl-NECA (4.17 +/- 0.06) and N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (IB-MECA) (3.7 +/- 0.02), and the A2A agonist 4-[(N-ethyl-5'-carbamoyladenos-2-yl)-aminoethyl]-phenylpropionic acid (CGS21680) (2.8 +/- 0.1). Because of the lack of a selective agonist, characterization of A2B receptor function is difficult in cells co-expressing A2A receptors. In the human mast cell line HMC-1, NECA induced cAMP accumulation with a concentration-response relationship best fitted to a two-sited model (pD2 7.69 +/- 0.42 and 5.92 +/- 0.21 for high- and low-affinity sites), suggesting the presence of both A2A and A2B receptors in these cells. We demonstrated that A2B receptors can be selectively activated with NECA in the presence of the selective A2A antagonist 5-amino-7-(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c ]pyrimidine (SCH 58261). Under these conditions, the concentration-response relationship of NECA for cyclic AMP accumulation was now best fitted to a one-site model (pD2 5.68 +/- 0.03, Hill slope 0.93 +/- 0.06, 95% confidence intervals 0.8 to 1.06) corresponding to selective activation of A2B receptors. Using the approaches developed in this study, we determined that A2B, and not A2A or A3, receptors account for all the calcium mobilization induced by NECA in HMC-1 cells.
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PMID:Pharmacological characterization of adenosine A2B receptors: studies in human mast cells co-expressing A2A and A2B adenosine receptor subtypes. 951 73


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