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

The experiments discussed above indicate that during immediate hypersensitivity reactions, macrophages are stimulated by mast cells to synthesize PGE2 and 6-keto-PGF1 alpha but not LTC4. The arachidonic acid utilized for these products is mobilized from the macrophages itself and not shuttled from the mast cells. The stimulus for the involvement of the macrophage does not appear to be a direct cell interaction between the two cell types or a soluble factor released by the mast cells. Since the profile of eicosanoids produced by macrophages when exposed to mast cell granules is similar to that observed in the contribution of macrophages to immediate hypersensitivity reactions, mast cell granules appear to be responsible for the recruitment of macrophages to this reaction.
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PMID:Nature of the mast cell-macrophage interaction in immediate hypersensitivity. 295 44

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

The effects of antiinflammatory steroids on arachidonic acid metabolite release from human lung fragments were analyzed. Incubation of lung fragments for 24 hr with 10(-6) M dexamethasone inhibited the net release of the prostacyclin metabolite 6-keto-PGF1 alpha, PGE2, and PGF2 alpha from lung fragments stimulated with anti-IgE but failed to inhibit the anti-IgE-induced release of PGD2, TXB2, and iLTC4. The IC50 of dexamethasone for inhibition of both spontaneous and anti-IgE-induced 6-keto-PGF1 alpha release was approximately 2 X 10(-8) M, and a 6-hr preincubation with the drug was required for 50% inhibition of prostaglandin release. Other agents were tested for activity in stimulating arachidonic acid metabolite release from human lung fragments. FMLP (fmet-leu-phe) stimulated the release of all metabolites tested (6-keto-PGF1 alpha, PGD2, PGE2, PGF2 alpha, TXB2, iLTC4); platelet-activating factor (PAF), but not lysoPAF, stimulated the release of PGD2, TXB2, and iLTC4. In contrast to the case with anti-IgE, where dexamethasone failed to inhibit net PGD2 and TXB2 release, the steroid inhibited the release of these metabolites stimulated by both FMLP and PAF. The steroid inhibited iLTC4 release induced by the highest concentration of PAF (10(-6)M) but did not inhibit iLTC4 release stimulated by either 10(-7) M PAF, FMLP, or anti-IgE. Because neither FMLP nor PAF caused the release of PGD2 or TXB2 from purified human lung mast cells, and because they also failed to induce histamine release from lung fragments, it is suggested that these stimuli produce PGD2 and TXB2 release in lung fragments through an action on a cell distinct from the mast cell. This suggestion is supported by the selective inhibition of the release of these arachidonic acid metabolites by dexamethasone. We suggest that the inhibitory action of steroids on arachidonic acid metabolite in human lung fragments contributes to their therapeutic efficacy in pulmonary diseases.
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PMID:Selective inhibition of arachidonic acid metabolite release from human lung tissue by antiinflammatory steroids. 308 76

Treatment for 24 h in vitro with dexamethasone inhibited the antigen-induced contractile response in guinea pig tracheal rings and parenchymal strips without inhibiting the contractile response of the tissues to either methacholine or histamine, respectively. Antigen-induced histamine release was inhibited by approximately 50% in both tissues by prior treatment with dexamethasone. Dexamethasone treatment also inhibited the release of immunoreactive sulfidopeptide leukotriene from parenchymal strips. In tracheal rings, dexamethasone treatment reduced spontaneous release of all cyclooxygenase metabolites (PGE2, PGF2 alpha, TXB2, PGD2, and 6-k-PGF1 alpha were tested), with the exception of PGD2, and also inhibited the antigen-induced release of all cyclooxygenase metabolites studied. Dexamethasone-treatment did not inhibit the spontaneous release of cyclooxygenase metabolites in the guinea pig lung strips, and only modestly inhibited the antigen-induced release of PGE2, PGF2 alpha, and PGD2. The results suggest that the inhibition of contractile response of guinea pig lung strips and airway tissue to antigen by dexamethasone is the result of a reduced release of inflammatory mediators. The inhibition by dexamethasone of antigen-induced release of mast cell mediators from guinea pig lung parenchyma contrasts with results previously obtained with human parenchymal lung tissue.
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PMID:Dexamethasone inhibits the antigen-induced contractile activity and release of inflammatory mediators in isolated guinea pig lung tissue. 310 4

Exposure to ethanol in man has been linked to an alteration of the immune surveillance system and reduced ability of the macrophage to undergo phagocytosis. Since ethanol has been suggested to alter membrane function and inhibit the production of calcium ionophore stimulated synthesis of prostaglandins and leukotrienes by the human neutrophil and transformed murine mast cell, the dose response effect of ethanol on the biosynthesis of icosanoids by the peritoneal macrophage during zymosan phagocytosis was studied. Peritoneal macrophages from two inbred strains of mice derived from a common stock (HS) and selected for sensitivity to ethanol (short sleep [SS]/long sleep [LS]) were studied. Zymosan phagocytosis was found to lead to synthesis of LTC4 (70 ng/10(6) cells), 6-keto-PGF1 alpha (5 ng/10(6) cells) and PGE2 (3 ng/10(6) cells). For the HS macrophage, ethanol caused a dose dependent inhibition of these lipid mediators as well as inhibition of phagocytosis and release of beta-hexosaminidase. However, a difference was observed in arachidonate metabolism stimulated by phagocytosis between the LS and SS mice below 100 mM ethanol. The SS mouse had a 50% inhibition of cyclooxygenase products at 86 mM ethanol with no inhibition of lipoxygenase metabolites. The LS mice had a trend suggesting increased lipoxygenase metabolites below 100 mM ethanol. At these levels of ethanol which can be found in man, these results suggest there may be differential production of lipid mediators under genetic control.
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PMID:The effect of ethanol on arachidonic acid metabolism in the murine peritoneal macrophage. 311 Aug 61

The synthetic PGE1 analog, misoprostol, was shown to have a marked inhibitory effect on gastric secretion as determined in the isolated gastric fundus from immature rats. It inhibited both the unstimulated and pentagastrin-stimulated acid secretion at 10(-7)-10(-4) molar concentrations. Its effect was different from that of PGE1 and PGE2, which did not affect basal acid secretion (up to 3 x 10(-5) M), although they inhibited to the same extent as misoprostol the pentagastrin-induced acid secretion. When given by "mucosal" application, misoprostol (10(-7)-10(-5) M) behaved similar to the mast cell stabilizer, compound FPL 52694, but its maximum reduction response was only 50%. The above data suggest that misoprostol has additional antisecretory mechanisms of action not shared by the classical natural prostaglandins.
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PMID:Inhibitory effect of misoprostol on gastric acid secretion in vitro. Qualitative differences from natural prostaglandins. 313 78

Primary cultures of adherent rheumatoid synovial cells contain variable proportions of fibroblasts, macrophages, and dendritic cells, as judged by morphological appearance. Comparative studies using various enzymic and histochemical staining procedures showed the dendritic cells to lack many of the characteristic features of macrophages, e.g. the failure to express HLA-DR (Ia) antigen. The dendritic cells and fibroblasts had several similarities, but differed to some extent in their nonspecific esterase activity, phagocytic and proliferative potential. As the proportions of dendritic cells and fibroblasts varied in relation to specific culture conditions, we examined the possibility that these morphologies might represent different functional states rather than distinct cellular origins. Using subcultured synovial fibroblasts with a uniform bipolar appearance, we have shown that exposure to interleukin-1 or mast cell products resulted in a transformation to dendritic morphology. This change in cell shape was prevented by the presence of indomethacin, but was subsequently achieved by the addition of exogenous PGE2. Thus it appears that the latter is the factor that modulates the morphological change of fibroblastic to dendritic cells. This study has also demonstrated the complete and reversible interchange of fibroblast/dendritic morphology, thereby confirming that these different shapes are manifest by the same cell. The changes in phenotypic expression associated with the dendritic appearance include increased production of collagenase, prostaglandin E, and nonspecific esterase, as well as an apparent inability to exhibit phagocytosis and to proliferate in culture. We conclude from our in vitro studies that the phenotypic behaviour of the synovial fibroblast (or synoviocyte) is very variable and dependent to a large extent upon local stimuli, but the identity and hierarchy of such stimulating and suppressive factors in relation to cellular interactions requires further study.
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PMID:Comparative studies of adherent rheumatoid synovial cells in primary culture: characterisation of the dendritic (stellate) cell. 349 52

1-0-Alkyl-2-Acetyl-sn-Glycero-3-Phosphocholine (AGEPC) produced dose-dependent (75-500 ng/site) increases in cutaneous vascular permeability (CVP) in rats as measured by extravasation of Evans blue dye. In contrast, lyso-AGEPC, at 1000 ng/site, was without effect. Pyrilamine, methysergide, and phenoxybenzamine, antagonists of mast-cell derived mediators, did not affect the AGEPC-induced increase in CVP. Likewise, agents capable of inhibiting mast cell mediator release, such as disodium cromoglycate, PRD-92-EA, theophylline, or nifedipine, had no effect. The cyclooxygenase inhibitor indomethacin produced significant inhibition of the response to AGEPC, whereas the lipoxygenase inhibitor nordihydroguiaretic acid (NDGA) and the peptide leukotriene antagonist FPL 55712 were without effect. The response to AGEPC was enhanced by the vasodilator PGE2 and inhibited by the vasoconstrictor phenylephrine. The selective AGEPC antagonist CV-3988 provided marked inhibition of the response. Unaccountably, the combination of indomethacin and CV-3988 provided no greater inhibition of the responses than either agent alone. These observations indicate that the AGEPC-induced increase in CVP in rats is mediated in part by products of the cyclooxygenase pathway and in part by activation of an AGEPC receptor.
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PMID:Pharmacologic analysis of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine-induced increases in cutaneous vascular permeability in the rat. 357 57

Purified human lung mast cells released histamine, leukotrienes, prostaglandin (PG) D2, thromboxane B2 (TxB2), and PGF2 alpha in response to anti-IgE stimulation. Incubation of the cells for 24 h with 10(-6) M dexamethasone, a treatment that inhibits mediator release from human basophils, had no effect on the release of these mediators from mast cells. Dexamethasone treatment of human lung fragments led to little or no inhibition of anti-IgE-induced release of the mast cell-derived mediator, histamine, but produced a significant inhibition of the release of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. As was the case with purified mast cells, the steroid did not inhibit the release of PGD2 or TxB2 from human lung fragments. Comparison of the quantities of PGD2 and TxB2 produced by purified cells and human lung fragments reveals that the mast cells produce quantities of these metabolites sufficient to account for the entire amount produced by challenged lung fragments. Dexamethasone inhibited spontaneous release from lung fragments of all cyclooxygenase products measured. These results suggest that the human lung parenchymal mast cell phospholipase is not inhibited by dexamethasone, whereas other phospholipase(s) in the lung are inhibited by the steroid. These results may be useful in explaining the resistance of acute allergic reactions, including anaphylaxis, to steroids, despite the potent antiinflammatory activity of steroids on subacute and chronic inflammation, such as in bronchial asthma, which may be initiated by IgE-dependent mechanisms.
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PMID:Effects of dexamethasone on mediator release from human lung fragments and purified human lung mast cells. 613 55

The production of five prostanoids (PGD2, PGE2, PGF2 alpha, 6-oxo-PGF1 alpha, and TxB2) was examined after mast cell activation. Prostaglandin D2 (PGD2) was the major prostanoid produced after stimulation of rat peritoneal mast cells with the calcium ionophore A 23187, compound 48/80 or anti-rat IgE. The amount of PGD2 generated was not dependent on the quantity of histamine released. The time course of PGD2 production paralleled the release of histamine following activation with A 23187 or anti-rat IgE but with compound 48/80 release of histamine reached a maximum within 15 sec, whereas production of PGD2 was apparent only after 5 min and was still increasing at 30 min.
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PMID:Prostaglandin and histamine release from stimulated rat peritoneal mast cells. 620 56


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