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)

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

This study aim was to assess the effects of rebamipide on the mechanism of histamine release and biosynthesis and release of leukotrienes caused by mast cell activation. We purified mast cells from guinea pig lung tissues by the use of enzyme digestion, the rough and the discontinuous density percoll gradient method. Mast cells were sensitized with IgG1 (anti-OVA) antibody and challenged with ovalbumin. Mast cells were also stimulated with A23187 and the intracellular Ca(2+) level was measured. Histamine and leukotrienes were measured by automated fluorometric analyzer and radioimmunoassay, respectively. The intracellular Ca(2+) level was analyzed using a confocal laser scanning microscope. Protein kinase C (PKC) activity was determined by protein phosphorylated with [gamma-(32)P]ATP. The phospholipase D activity was assessed by the labeled phosphatidylalcohol. Mass 1,2-diacylglycerol (DAG) was measured by the [(3)H]DAG produced when prelabeled with [(3)H]myristic acid. PLA(2) activity was determined by measuring the arachidonic acid released from the labeled phospholipids. Rebamipide decreased the releases of histamine and leukotrienes, and completely blocked Ca(2+) influx during mast cell activation by antigen-antibody reactions. It also decreased the release of histamine and leukotrienes during mast cell activation by A23187. The PKC and PLD activities were also decreased by rebamipide in a dose-dependent manner. Rebamipide inhibited the mass DAG production and PLA(2) activity during mast cell activation. The data suggest that rebamipide inhibits intracellular signals and blocks Ca(2+) influx in mast cells activated by specific antigen-antibody reactions, which in turn inhibits histamine release and leukotriene generation.
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PMID:The inhibitory mechanism of rebamipide on the mediator release in the guinea pig lung mast cells activated with specific antigen-antibody reactions. 1159 24

We recently characterized a heparin-deficient mouse strain generated by targeting the gene for N-deacetylase/N-sulfotransferase-2 (NDST-2). The NDST-2-/- mice show severe defects in their organization of mast cell (MC) secretory granules, with an almost total absence of the various heparin-binding MC proteases. In the present report we have studied the consequences of heparin/MC protease deficiency for extravascular coagulation and fibrinolysis. Addition of prothrombin to peritoneal cells-a mixture of macrophages, lymphocytes, and MCs-resulted in formation of thrombin but the accumulation of thrombin occurred faster in the NDST-2-/-cells than in normal controls. Further, the generated thrombin was subsequently inactivated in the NDST-2+/+ cell cultures but not in the NDST-2-/- cells. Plasminogen was activated to plasmin at an apparently higher rate in peritoneal cells from NDST-2 null mice than in the normal controls. Similar to thrombin, the generated plasmin was inactivated by NDST-2+/+ but not by the NDST-2-/- cells. Subsequent experiments with normal cells showed that cell surface-associated MC chymase, in a strongly heparin-dependent manner, was responsible for both the thrombin-inactivating- and plasmin-inactivating activities. These results show that MC chymase-heparin complexes have the potential to regulate extravascular coagulation processes, as well as the plasminogen activator/plasmin system.
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PMID:Regulation of extravascular coagulation and fibrinolysis by heparin-dependent mast cell chymase. 1168 8

Phospholipases A(2) (PLA(2)s), of molecular mass 13-15kDa, are commonly isolated from snake venom. Two myotoxins with PLA(2) activity, BaPLA(2)I and BaPLA(2)III, with estimated molecular masses of 15kDa were isolated from the venom of Bothrops atrox using Sephacryl S-100-HR and reverse-phase chromatography. BaPLA(2)I was basic, with a pI of 9.1, while BaPLA(2)III was neutral with a pI of 6.9. On a molecular basis, BaPLA(2)III exhibited higher catalytic activity on synthetic substrates than BaPLA(2)I. Comparison of the N-terminal residues of BaPLA(2)I with other PLA(2) proteins from snake venoms showed that it has the highest homology (94%) with B. asper myotoxin II and homology with a PLA(2) Lys(49) from B. atrox (89%). In contrast, BaPLA(2)III demonstrated 75, 72, and 71% homology with PLA(2) from Vipera ammodytes meridionalis, B. jararacussu, and B. jararaca, respectively. BaPLA(2)I and BaPLA(2)III were capable, in vitro, of inducing mast cell degranulation and, in vivo, of causing creatine kinase release, edema, and myonecrosis typical of PLA(2)s from snake venoms, characterized by rapid disruption of the plasma membrane as indicated by clumping of myofilaments and necrosis of affected skeletal muscle cells. BaPLA(2)I- and BaPLA(2)III-specific monoclonal and polyclonal antibodies, although incapable of neutralizing PLA(2) edematogenic activity, blocked myonecrosis efficiently in an in vivo neutralization assay. The results presented herein suggest that the biological active site responsible for edema induction by these two PLA(2) enzymes is distinct from the myonecrosis active site and is not dependent upon the catalytic activity of the PLA(2) enzyme.
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PMID:Biochemical and biological properties of phospholipases A(2) from Bothrops atrox snake venom. 1223 22

Recent studies have suggested that dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) may be more beneficial in the treatment of inflammatory diseases in which platelet-leukocyte interaction dominates the underlying inflammatory process, than inhibitors of COX or LO alone. In this study, we examined oxygenated xanthones, shown previously to inhibit platelet and neutrophil activation, with respect to the potency of COX inhibition. 1,3,6,7-Tetrahydroxyxanthone (norathyriol) was the most potent. Norathyriol suppressed thromboxane B(2) (TXB(2)) and leukotriene B(4) (LTB(4)) formation in calcium ionophore (A23187)- and formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rat neutrophils. Norathyriol was 3-4 times more active against LTB(4) formation than against TXB(2) formation (IC(50) about 2.8 vs. 10 microM, respectively). Norathyriol also inhibited prostaglandin D(2) (PGD(2)) formation in A23187-stimulated rat mast cells (IC(50) 3.0+/-1.2 microM) and in arachidonic acid (AA)-activated mast cell lysate. Norathyriol was a more effective inhibitor of 5-LO activity than of COX, as shown also by analyses of enzyme activities in a cell-free system, of COX and 5-LO metabolic capacity in neutrophils and of ex vivo TXB(2) and LTB(4) formation in A23187-stimulated neutrophils. Moreover, norathyriol inhibited COX-2 and 12-LO with IC(50) values (19.6+/-1.5 and 1.2+/-0.1 microM, respectively) similar to those required for the inhibition of COX-1 and 5-LO (16.2+/-1.5 and 1.8+/-0.4 microM, respectively). Inhibition of 15-LO by norathyriol was slightly less active. Norathyriol had no effect on A23187-induced AA release from neutrophils and did not affect phospholipase A(2) (PLA(2)) activity in a cell-free system. These results indicate that norathyriol inhibits the formation of PGs and LTs in neutrophils probably through direct blockade of COX and 5-LO activities. Norathyriol, a single molecule with multiple targets, might provide a potential therapeutic benefit in the treatment of inflammatory diseases.
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PMID:Inhibition of the arachidonic acid cascade by norathyriol via blockade of cyclooxygenase and lipoxygenase activity in neutrophils. 1508 66

Increased mast cell numbers and mast cell activation represent one of the prevalent etiologic theories for interstitial cystitis, an inflammatory condition in the bladder. This study was designed primarily to determine whether increased mast cell tryptase in the bladder wall may play a role in activating bladder endothelial cell phospholipase A(2) (PLA(2)), leading to increased inflammatory phospholipid metabolite accumulation, which may propagate the inflammatory process. We stimulated human bladder microvascular endothelial cells with thrombin or tryptase and measured the activation of PLA(2) and the production of multiple membrane phospholipid-derived inflammatory mediators. Thrombin and tryptase stimulation resulted in activation of a Ca(2+)-independent PLA(2), leading to increased release of arachidonic acid and prostacyclin and increased production of platelet-activating factor. These responses were blocked completely by pretreatment of human bladder microvascular endothelial cells with the Ca(2+)-independent PLA(2)-selective inhibitor bromoenol lactone. The combination of increased prostacyclin and platelet-activating factor in the bladder circulation may result in vasodilation and increased polymorphonuclear leukocyte adherence to the endothelium and may facilitate recruitment of polymorphonuclear leukocytes to the bladder wall of patients with interstitial cystitis.
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PMID:Protease-activated receptor stimulation activates a Ca2+-independent phospholipase A2 in bladder microvascular endothelial cells. 1556 75

Mast cells are detrimental in several inflammatory diseases; however, their physiological roles are also increasingly recognized. Recent data suggest that mast cells may also be involved in renal diseases. We therefore used congenitally mast cell-deficient W/W(v) mice and normal +/+ littermates to assess their role in anti-glomerular basement membrane-induced glomerulonephritis. Following administration of anti-glomerular basement membrane Abs, W/W(v) mice exhibited increased mortality as compared with +/+ mice owing to rapid deterioration of renal function. Reconstitution of the mast cell population in W/W(v) mice restored protection. This was independent of activating FcgammaR, as protection was also obtained using mast cells deficient in FcRgamma. Comparative histological analysis of kidneys showed that deterioration of renal function was caused by the presence of thick layers of subendothelial glomerular deposits in W/W(v) mice, while +/+ mice or mast cell-reconstituted W/W(v) mice showed significantly less. Deposits appeared during the early phase of disease and persisted thereafter, and were accompanied by enhanced macrophage recruitment. Immunohistochemical analysis revealed increased amounts of fibrin and type I collagen in W/W(v) mice, which were also unable to maintain high tissue plasminogen activator and urinary-type plasminogen activator activity in urine in the heterologous phase of disease. Our results indicate that mast cells by their ability to mediate remodeling and repair functions are protective in immune complex-mediated glomerulonephritis.
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PMID:Mast cell-mediated remodeling and fibrinolytic activity protect against fatal glomerulonephritis. 1684 39

Interstitial cystitis (IC) is associated with increased activated mast cell numbers in the bladder and impairment of the barrier function of the urothelium. We stimulated immortalized urothelial cells derived from the inflamed region of IC bladders (SR22A or SM28 abn) or from healthy bladders (PD07i or PD08i) with tryptase and measured phospholipase A(2) (PLA(2)) activity and the resultant release of arachidonic acid and prostaglandin E(2) (PGE(2)). Tryptase stimulation of either PD07i or SR22A resulted in similar increases in PLA(2) activity and arachidonic acid release. However, tryptase stimulation of SR22A and SM28 abn did not result in a significant increase in PGE(2) release compared with the increase in PGE(2) release from tryptase-stimulated PD07i and PD08i cells. Expression of mRNA for cyclooxygenase-2 and PGE synthase was lower and mRNA for 15-hydroxyprostaglandin dehydrogenase was higher in SR22A compared with PD07i, suggesting that both decreased synthesis and increased metabolism are responsible for the lack of a PGE(2) response in tryptase-stimulated SR22A cells. Since PGE(2) is a cytoprotective eicosanoid, the failure to produce this metabolite in cells isolated from the IC bladder may represent an increased susceptibility to damage by proinfammatory stimuli.
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PMID:Loss of prostaglandin E2 release from immortalized urothelial cells obtained from interstitial cystitis patient bladders. 1832 19

We report on a patient with coagulation abnormalities induced by a wasp sting anaphylaxis. First, we observed an unclottable activated partial thromboplastin time and a significant anti-Xa activity (equivalent to a therapeutic heparin range), whereas the patient had received no heparin. This phenomenon is probably due to activated mast cells that release mediators such as heparin and tryptase. Heparin can then act as an anticoagulant by binding to antithrombin. This "heparinization" explains the anti-Xa activity contributing to the unclottable activated partial thromboplastin time detected in our patient. Second, we noted an extremely low fibrinogen level in the presence of normal platelet count and only a slight increase of D-dimers (absence of important disseminated intravascular coagulation). This is probably due to serum tryptase released during massive mast cell activation. Tryptase cleaves the alpha and beta chains of fibrinogen. This results in the removal of the thrombin cleavage site and of the critical polymerization site from the fibrinogen beta chain. Thrombin- initiated clot formation is therefore inhibited. Tryptase also acts directly on the fibrinolytic pathway by activating the single-chain urinary-type plasminogen activator, resulting in conversion of plasminogen into plasmin and therefore degradation of fibrinogen and other coagulation factors. This hyperfibrinogenolysis explains both the prolonged clotting times and the low fibrinogen level observed. Although our patient did not bleed, in other settings (trauma, during surgery) patients with anaphylaxis may present bleeding disorders. Although the mechanisms underlying these abnormalities have been described in vitro and in vivo animal trials, this is the first time they are described in a human clinical setting.
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PMID:"Heparinization" and hyperfibrinogenolysis by wasp sting. 2207 26

It has been recognized that phospholipase A(2) (PLA(2)) is a crucial factor of snake venom induced inflammation. Recently, promutoxin, a novel member of minor subgroup of snake venom PLA(2) (R49 PLA(2)) has been characterized in our laboratory, but its roles in induction of inflammation remain uninvestigated. Using highly purified promutoxin, we found this enzymatically inactive PLA(2) provoked a dose-dependent increase in microvascular leakage in the skin of rats. Pretreatment of rats with compound 48/80 diminished promutoxin-induced skin reaction and reduced mast cell numbers in rats. Cyproheptadine, terfenadine, Ginkgolide B and heparin inhibited promutoxin elicited microvascular leakage when they were co-injected with the stimulus to rat skin. Moreover, promutoxin was found to induce histamine release from human colon, lung and tonsil mast cells, and both metabolic inhibitors and pertussis toxin were capable of inhibiting promutoxin elicited histamine release. Provocation of microvascular leakage and mast cell activation by promutoxin suggests further that snake venom induced inflammation is related to mast cell activation and certain anti-inflammatory drugs could be therapeutic effective in treating snake wound.
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PMID:Induction of microvascular leakage and histamine release by promutoxin, an Arg49 phospholipase A2. 2003 73


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