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)

Cytosolic phospholipase A(2) (cPLA(2)) plays a critical role in mast-cell-related allergic responses [Uozumi, Kume, Nagase, Nakatani, Ishii, Tashiro, Komagata, Maki, Ikuta, Ouchi et al. (1997) Nature (London) 390, 618-622]. Bone-marrow-derived mast cells from mice lacking cPLA(2) (cPLA(-/-)(2) mice) were used in order to better define the role of cPLA(2) in the maturation and degranulation of such cells. Cross-linking of high-affinity receptors for IgE (FcepsilonRI) on cells from cPLA(-/-)(2) mice led to the release of negligible amounts of arachidonic acid or its metabolites, the cysteinyl leukotrienes and prostaglandin D(2), indicating an essential role for cPLA(2) in the production of these allergic and pro-inflammatory lipid mediators. In addition, the histamine content of the mast cells and its release from the cells were reduced to 60%. While these results are in agreement with a reduced anaphylactic phenotype of cPLA(-/-)(2) mice, the ratios of release of histamine and beta-hexosaminidase were, paradoxically, significantly higher for cells from cPLA(-/-)(2) mice than for those from wild-type mice. Consistently, IgE-induced calcium influx in mast cells was greater and more prolonged in cells from cPLA(-/-)(2) mice than in those from wild-type mice. Thus the loss of cPLA(2) not only diminishes the release of lipid mediators, but also alters degranulation. While the overall effect is still a decrease in the release of mast cell mediators, explaining the in vivo findings, the present study proposes a novel link between cPLA(2) and the degranulation machinery.
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PMID:Role of cytosolic phospholipase A2 in the production of lipid mediators and histamine release in mouse bone-marrow-derived mast cells. 1108 23

According to most textbooks, diagnostic tests with Hymenoptera venoms are reliable, and immunotherapy with these venoms in Hymenoptera-venom-allergic patients leads in near to 100% to full protection. Careful analysis of the literature shows however that the specificity of diagnostic tests is far from perfect and that both efficacy and tolerance, especially in patients receiving honeybee venom immunotherapy, are still suboptimal. The major allergens of honeybee and vespid venoms are now available in recombinant form. Preliminary trials analyzing diagnostic tests with recombinant allergens in honeybee venom allergy are promising: the specificity is clearly increased in both skin testing and in determining venom-specific IgE antibodies when compared to natural venom allergens. An important recent finding is the frequent association of severe Hymenoptera venom allergy and elevated basal serum levels of the mast-cell-specific enzyme tryptase. Elevated levels are found in up to 30% of the patients with a history of severe shock reactions following Hymenoptera stings. The current findings indicate that basal tryptase levels indicating an increased mast cell load are much more frequent than previously thought and are a risk factor for severe or even fatal sting reactions. Premedication with antihistamines in the initial phase of venom immunotherapy reduced both local and systemic allergic side effects in several controlled studies. In a retrospective analysis of one of these trials it was found that reexposure during immunotherapy resulted in significantly more systemic allergic reactions in patients on placebo than on antihistamine premedication, suggesting that initial antihistamine premedication might increase the efficacy of venom immunotherapy. Different ways of allergen modification for venom immunotherapy have been proposed. While the results with chemical modifications were not convincing, recent studies with T-cell epitope peptides from the major bee venom allergen phospholipase A(2) look promising. Patient-tailored cocktails of recombinant venom allergens or isoforms thereof may be another possibility in the future. A number of prospective studies analyzing the duration of venom immunotherapy required for long-term protection have been published in the last decade. While most patients are still fully protected 1 year after discontinuation of therapy, relapses may occur in up to 20% of patients reexposed many years after treatment. Various risk factors for such relapses have been identified.
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PMID:New developments in the diagnosis and treatment of hymenoptera venom allergy. 1134 Mar 27

Lysophosphatidylserine (1-acyl-2-lyso-PS) has been shown to stimulate histamine release from rat peritoneal mast cells (RPMC) triggered by FcepsilonRI (high affinity receptor for IgE) cross-linking, although the precise mechanism of lyso-PS production has been obscure. In the present study we show that phosphatidylserine-specific phospholipase A(1), PS-PLA(1), stimulates histamine release from RPMC through production of 2-acyl-1-lyso-PS in the presence of FcepsilonRI cross-linker. The potency of 2-acyl-1-lyso-PS was almost equal to that of 1-acyl-2-lyso-PS. A catalytically inactive PS-PLA(1), in which an active serine residue (Ser(166)) was replaced with an alanine residue did not show such activity. sPLA(2)-IIA, another secretory PLA(2) that is capable of producing lyso-PS in vitro, was also a poor histamine inducer against RPMC. PS-PLA(1) significantly stimulated histamine release from crude RPMC, indicating that lyso-PS is mainly derived from cells other than mast cells. In agreement with this phenomenon, the enzyme stimulated the histamine release more efficiently when RPMC were mixed with apoptotic Jurkat cells. Under these conditions, lyso-PS with unsaturated fatty acid was released from the apoptotic cells treated with PS-PLA(1). Finally, heparin, which has affinity for PS-PLA(1), completely blocked the stimulatory effect of the enzyme. In conclusion, PS-PLA(1) may bind to heparan sulfate proteoglycan, efficiently hydrolyze PS appearing on plasma membranes of apoptotic cells, and stimulate mast cell activation mediated by 2-acyl-1-lyso-PS.
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PMID:Phosphatidylserine-specific phospholipase A1 stimulates histamine release from rat peritoneal mast cells through production of 2-acyl-1-lysophosphatidylserine. 1139 20

Biological membranes contain an extraordinary diversity of lipids. Phospholipids function as major structural elements of cellular membranes, and analysis of changes in the highly heterogeneous mixtures of lipids found in eukaryotic cells is central to understanding the complex functions in which lipids participate. Phospholipase-catalyzed hydrolysis of phospholipids often follows cell surface receptor activation. Recently, we demonstrated that granule fusion is initiated by addition of exogenous, nonmammalian phospholipases to permeabilized mast cells. To pursue this finding, we use positive and negative mode Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS) to measure changes in the glycerophospholipid composition of total lipid extracts of intact and permeabilized RBL-2H3 (mucosal mast cell line) cells. The low energy of the electrospray ionization results in efficient production of molecular ions of phospholipids uncomplicated by further fragmentation, and changes were observed that eluded conventional detection methods. From these analyses we have spectrally resolved more than 130 glycerophospholipids and determined changes initiated by introduction of exogenous phospholipase C, phospholipase D, or phospholipase A2. These exogenous phospholipases have a preference for phosphatidylcholine with long polyunsaturated alkyl chains as substrates and, when added to permeabilized mast cells, produce multiple species of mono- and polyunsaturated diacylglycerols, phosphatidic acids, and lysophosphatidylcholines, respectively. The patterns of changes of these lipids provide an extraordinarily rich source of data for evaluating the effects of specific lipid species generated during cellular processes, such as exocytosis.
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PMID:Electrospray ionization mass spectrometry analysis of changes in phospholipids in RBL-2H3 mastocytoma cells during degranulation. 1141

This study tested the hypothesis that certain secretory phospholipase A(2) (sPLA(2)) isotypes act in a cytokine-like fashion through cell surface receptors to influence mast cell survival. Initial experiments revealed that sPLA(2) activity and sPLA(2) receptor expression are increased, and mast cells lost their capacity to maintain membrane asymmetry upon cytokine depletion. Groups IB and III, but not group IIA PLA(2), prevented the loss of membrane asymmetry. Similarly, group IB prevented nucleosomal DNA fragmentation in mast cells. Providing putative products of sPLA(2) hydrolysis to cytokine-depleted mast cells did not influence survival. Furthermore, catalytic inactivation of sPLA(2) did not alter its capacity to prevent apoptosis. Inhibition of protein synthesis using cycloheximide or actinomycin reversed the antiapoptotic effect of sPLA(2). Additionally, both wild-type and catalytically inactive group IB PLA(2) induced IL-3 synthesis in mast cells. However, adding IL-3-neutralizing Ab did not change Annexin V(FITC) binding and only partially inhibited thymidine incorporation in sPLA(2)-supplemented mast cells. In contrast, IL-3-neutralizing Ab inhibited both Annexin V(FITC) binding and thymidine incorporation in mast cells maintained with IL-3. sPLA(2) enhanced phosphoinositide 3'-kinase activity, and a specific inhibitor of phosphoinositide 3'-kinase reversed the antiapoptotic effects of sPLA(2). Likewise, sPLA(2) increased the degradation of I-kappaBalpha, and specific inhibitors of nuclear factor kappa activation (NF-kappaB) reversed the antiapoptotic effects of sPLA(2). Together, these experiments reveal that certain isotypes of sPLA(2) enhance the survival of mast cells in a cytokine-like fashion by activating antiapoptotic signaling pathways independent of IL-3 and probably via sPLA(2) receptors rather than sPLA(2) catalytic products.
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PMID:Enhancement of mast cell survival: a novel function of some secretory phospholipase A(2) isotypes. 1159 36

In the present study, the effect of ceramide on antigen-stimulated phosphorylation of extracellular signal-regulated kinase (ERK) in the mechanism responsible for regulating production of prostaglandin (PG) D(2) was investigated in the mast cell line, RBL-2H3 cells. Cell-permeable C(6)-ceramide (N-hexanoylsphingosine) suppressed antigen-stimulated phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase. Ceramide also inhibited production of PGD(2) and an increase in the activity of cytosolic phospholipase A(2) (cPLA(2)), whereas it did not influence the tyrosine phosphorylation of major cellular proteins in response to antigen. The ceramide-induced inhibition of ERK1/2 phosphorylation and of cPLA(2) activation was suppressed by orthovanadate, a tyrosine phosphatase inhibitor, but not by okadaic acid, a serine/threonine phosphatase inhibitor. Addition of ceramide to the lysate prepared from antigen-stimulated cells reduced the phosphorylated ERK1/2, and orthovanadate effectively prevented the reduction. These results suggest that ceramide accelerates the dephosphorylation of phosphorylated ERK1/2 via activation of a protein tyrosine phosphatase, thus preventing activation of cPLA(2) and production of PGD(2).
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PMID:Ceramide accelerates dephosphorylation of extracellular signal-regulated kinase 1/2 to decrease prostaglandin D(2) production in RBL-2H3 cells. 1169 58

Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin.
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PMID:The pharmacological profile of ovalbumin-induced paw oedema in rats. 1213 44

We present Simple Intrasequence Difference (SID) analysis, a novel bioinformatic technique designed to help comprehend the properties of protein fold topologies. The analysis grades numerically every residue position in a given protein 3D structure according to the topological situation of the position in the folded chain. This results in an expression of the potential contribution of each residue position and its vicinity towards the integrity of the molecular conformation. Contiguous highly graded residues delineate the sub-structural interfaces that arise from the presence within the molecular fold of discrete domains and sub-domains. This comprehensive rendering of the internal arrangement of chain interfacing helps predict the potential for site-specific inductions (e.g. via mutations or ligand binding) of conformational change in the fold. Whereas SID analysis of single folds can convey an idea of the basic potential for topological adjustment in the protein family, comparative SID analysis of related folds focuses attention on those areas of the family fold where evolutionary changes, activation events and ligand binding have had the most topological impact. For demonstration, SID analysis is applied to the folds of pancreatic trypsin inhibitor (Kunitz), phospholipase A(2), chymotrypsin and carboxypeptidase A. We find that many of the potentially vulnerable sub-structural interfaces tend to be protected in the fold interior, in many cases stabilised by disulfide bridges spanning the interface. However, the most prominent interfaces tend to be externally accessible, without remedial stabilisation by disulfide bridges. These latter interfaces are associated so closely with the known functional sites that alterations to the interfacial juxtapositions should influence recognition and catalytic behaviour directly. This shows how side chain mutations, chemical modifications and binding events remote from the sites can nevertheless adjust, via interfacial realignment, the conformations and emergent properties of the sites. The close association also provides clear opportunities for interfacial rearrangements to follow intermolecular recognition events in the sites, facilitating translation of the binding into adjustment of the molecular conformation in areas distant from the sites. As a direct consequence of the topological arrangements, a large proportion of the molecular structure has the capacity to shape the character of the functional sites and, conversely, binding at these sites has the potential to radiate influence to the rest of the molecule. For the enzymes considered, the evidence is consistent with the possibility that primary and secondary binding by the substrate enhances catalytic efficiency by imposing conformational change upon the catalytic centre via adjustments to the fold. This influence may be expressed as favourable adjustment of the catalytic geometry, transition state ensemble, energy propagation pathway, or as a physical strain exerted on the substrate bond to be cleaved. The scale of the adjustments, and their importance to the mechanisms, may have been seriously underestimated.
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PMID:Simple intrasequence difference (SID) analysis: an original method to highlight and rank sub-structural interfaces in protein folds. Application to the folds of bovine pancreatic trypsin inhibitor, phospholipase A2, chymotrypsin and carboxypeptidase A. 1267 77

Activation of cardiac mast cells has been shown to alter parasympathetic neuronal function via the activation of histamine receptors. The present study examined the ability of prostaglandins to alter the activity of guinea pig intracardiac neurons. Intracellular voltage recordings from whole mounts of the cardiac plexus showed that antigen-mediated mast cell degranulation produces an attenuation of the afterhyperpolarization (AHP), which was prevented by the phospholipase A2 inhibitor 5,8,11,14-eicosatetraynoic acid. Exogenous application of either PGD2 or PGE2 produced a biphasic change in the membrane potential and an inhibition of both AHP amplitude and duration. Examination of prostanoid receptors using bath perfusions (1 microM PGE2 and PGD2), specific agonists (BW245C, sulprostone, and butaprost), and antagonists (AH6809 and SC19220) found evidence for both the PGE2-specific EP2 and EP3 receptors, but not for EP1 or the PGD2-specific prostanoid (DP) receptors. Sulprostone was able to mimic the PGE2 responses in some cells, but not in all PGE2-sensitive cells. Butaprost was able to mimic the PG-induced hyperpolarization in some cells, but did not alter the AHP. Inhibition of specific potassium channels with either TEA, charybdotoxin, or apamin showed that neither TEA nor charybdotoxin could prevent the PGE2-induced AHP attenuation. Apamin alone inhibited AHP duration, with PGs having no further effect in these cells. These results demonstrate that guinea pig intracardiac neurons can be modulated by PG, most likely through either EP2, EP3, or potentially EP4 receptors, and this response is due, at least in part, to a reduction in small-conductance KCa currents.
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PMID:Modulation of guinea pig intrinsic cardiac neurons by prostaglandins. 1279 85

A novel quinolinone derivative, TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], has been shown to inhibit antigen-induced asthmatic responses including the early-phase bronchoconstriction in actively sensitized guinea pigs. Here we characterized the action mechanisms of TA-270 in cellular level in vitro. In RBL-2H3 mast cells sensitized with dinitrophenol (DNP)-specific IgE, the antigen exhibited several mast cell functions, including hexosaminidase release as a marker of degranulation, production of tumor necrosis factor-alpha, and production of immunologically detective leukotrienes. These antigen-induced actions were associated with the activation of several early signaling events, including inositol phosphate production reflecting phospholipase C activation and extracellular signal-regulated kinase activation. When the cells were treated with TA-270, the antigen-induced leukotriene production was almost completely suppressed, but other antigen-induced actions listed above were hardly affected. This drug also failed to affect the antigen-induced phospholipase A2 activation as evaluated by the total release of arachidonic acid and its metabolites from the cells prelabeled with radioactive arachidonic acid. However, TA-270 clearly changed the arachidonic acid metabolic pathway. It suppressed the accumulation of 5-lipoxygenase products, including leukotrienes, but hardly affected the accumulation of cyclooxygenase products. The inhibitory action of TA-270 on leukotriene production was also observed in human neutrophils and eosinophils. We conclude that TA-270 inhibits 5-lipoxygenase activity and, thereby, suppresses the antigen-induced leukotriene production.
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PMID:TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an anti-asthmatic agent, inhibits leukotriene production induced by IgE receptor stimulation in RBL-2H3 cells. 1297 Mar 84


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