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)

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

Prostaglandins and related compounds comprise an ubiquitous biological system which utilizes arachidonic acid (5,8,11,14-eicosatetraenoic acid) as a common cellular precursor to synthesize a great number of substances with a broad range of activities, including participation in the cellular and humoral events of inflammation and allergy. Briefly, prostaglandins and thromboxanes (TX) are formed in reactions initiated by the aspirin-sensitive fatty acid cyclooxygenase, whereas leukotrienes (LT) and several other compounds are generated by different lipoxygenases present in human tissues. In the field of asthma, the mast cell-derived PGD2 alpha, as well as PGF2 alpha and TXA2 are known as reasonably potent bronchoconstrictors, and asthmatics are remarkably hyperreactive to inhalation of PGF2 alpha. However, the therapeutic failure of aspirin and related cyclooxygenase inhibitors in the treatment of asthma suggests that these compounds are less likely to be primary mediators. On the other hand, several lines of evidence indicate that three closely related leukotrienes, LTC4, LTD4 and LTE4, previously known as slow-reacting substance of anaphylaxis (SRS-A), have the potential to be major mediators of the airway perturbations characteristic of bronchial asthma. Thus, as documented both in experimental animals and in man, these leukotrienes are exquisitely potent in causing bronchial smooth muscle contraction, mucosal edema, and secretion of mucus into the lumen. In particular, LTC4, LTD4 and LTE4 have been linked to allergic asthma because allergen challenge is a potent stimulus for their release from, e.g., lung tissue of asthmatics. In fact, it has been documented that inhibition of leukotriene formation can block allergen-induced contractions of isolated human bronchi.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Leukotrienes and other eicosanoids as mediators of airway obstruction. 356 14

Isolated, perfused kidneys from ovalbumin-sensitized guinea pigs released large amounts of histamine, thromboxane (TX) B2 and less consistently leukotriene (LT) C4, and showed a marked reduction in perfusion rate (PR) following injection of the specific antigen, or antiserum to IgG1 and IgG2; both types of anaphylactic reaction being due to cross-linking of mast cell-sensitizing immunoglobulin. Infusion of low concentration of synthetic LTC4 caused reduction in PR, which was blocked by the antagonist FPL 55712. Large-dose bolus injections of histamine also reduced PR. It is concluded that the kidney is a target organ in anaphylaxis and that the reaction alters renal haemodynamics.
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PMID:Release of thromboxane B2 and leukotriene C4 and reduction in renal perfusion in experimental anaphylactic reaction of isolated guinea pig kidney. 380 63

A neoplastic mast cell tumor was grown in mice which had been raised since birth on a diet enriched with eicosapentaenoic acid. Intact harvested mastocytoma cells were stimulated with calcium ionophore A23187 to produce lipoxygenase products from the polyunsaturated fatty acids liberated from the cellular membranes. Leukotriene B4, B5, C4, and C5 were isolated and characterized by HPLC retention time, ultraviolet absorption spectrometry and mass spectrometry. The arachidonic acid content of the mast cell tumor lipids was altered from 9.2 to 3.9 mole % while eicosapentaenoic acid increased from 0.5 to 4.5 mole % in response to the fish oil-supplemented diet. The relative amounts of arachidonic and eicosapentaenoic acids (3.9 and 4.5 mole % respectively) were associated with similar amounts of LTB4 and LTB5 synthesized by the cells. These results suggest that the epoxide leukotriene (LIA) derivative can be made efficiently from either arachidonic or eicosapentaenoic acids when both are present in cellular lipids. In contrast, the ratio of LTC4 to LTC5 (10 to 1) indicates that the reaction of LTA with glutathione may be critically dependent upon the structure of the unsaturated fatty acid with the ratio of LTC4/LTB4 (2.0) more than 10 times greater than that (0.16) for LTC5/LTB5.
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PMID:Tetraene and pentaene leukotrienes: selective production from murine mastocytoma cells after dietary manipulation. 611 40

Isolated dog mastocytoma cells sensitized with dog anti-ragweed IgE and challenged with ragweed antigen generate the C-6 peptide leukotriene (LT) constituents of the slow-reacting substance of anaphylaxis (SRS-A), LTC4 and LTD4, and the potent leukocyte chemotactic factor, LTB4, as well as 15-hydroxyeicosatetraenoic acid (15-HETE), 12-HETE, and 5-HETE. Antigen challenge evoked a mean maximum production of LTC4, LTD4, and LTB4, respectively, of 16.3 ng, 4.6 ng, and 6.7 ng per 10(6) mastocytoma cells within 5 min at 37 degrees C, which was maintained for up to 45 min. The maximum production of leukotrienes by mastocytoma cells activated with optimum concentrations of 0.2 to 1 microM calcium ionophore A23187 was 35% to 50% greater than that achieved by antigen challenge, without alterations in the relative quantities of leukotrienes, but was realized only after 30 min at 37 degrees C. The leukotriene products of mastocytoma cells were identified by high-performance liquid chromatography, spectral properties, and immunoreactivity with mono-specific antisera, and exhibited the same concentration-dependence of biologic activity as authentic synthetic standards. The ratio of quantities of C-6 peptide leukotrienes generated was attributable in part to the rate of peptidolytic conversion of LTC4 to LTD4 in the mastocytoma cells, which was 33% per 30 min at 37 degrees C. The rapid maximum response to IgE-dependent stimulation and the unique spectrum of products distinguishes the secretion of leukotrienes by dog mastocytoma cells from that by basophils and some other types of mast cells and suggests diverse contributions of mast cell leukotrienes to immediate and late hypersensitivity reactions.
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PMID:IgE-dependent and ionophore-induced generation of leukotrienes by dog mastocytoma cells. 630 9

We have studied the ability of leukotrienes and other lipoxygenase products of arachidonic acid (AA) to influence complement-dependent killing of schistosomula of Schistosoma mansoni in vitro by human neutrophils or eosinophils. These lipid mediators, which included LTB4, LTC4, LTD4, 5-HETE and 5-HPETE, had no apparent effect, by themselves, on schistosomular motility or viability. However, in the presence of granulocytes and fresh serum (as a source of complement) LTB4 (but not LTC4, LTD4, 5-HETE or 5-HPETE) enhanced neutrophil- and (to a much lesser extent) eosinophil mediated, complement-dependent killing. These effects varied with the concentration of LTB4, the dilution of complement and time of incubation. The percentage of LTB4-induced enhancement obtained with neutrophils was greater than that observed with eosinophils (although the latter were obtained from patients with helminthic parasitic disease). The synthetic bacterial analogue f-Met-Leu-Phe, also known to amplify complement associated granulocyte events, was comparable to LTB4 in its ability to enhance neutrophil- and eosinophil-mediated, complement-dependent killing of schistosomula. These results indicate that LTB4, which is released in mast cell associated reactions and promotes cell locomotion and enhancement of complement receptors in vitro, increases neutrophil- and eosinophil-mediated, complement-dependent damage of schistosomula, possibly through enhancement of C3b receptors and that this may be an important amplification mechanism in IgE related immunity to migrating helminthic larvae.
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PMID:Enhancement of neutrophil- and eosinophil-mediated complement-dependent killing of schistosomula of Schistosoma mansoni in vitro by leukotriene B4. 630 58

The events which lead to airway narrowing in bronchial asthma are complex. There is little doubt that mast cell-derived pharmacological agents are involved, at least in part, in the initiation of the asthmatic response. However, the inflammatory response which follows mast cell activation might have more relevance to the daily pattern of asthma than the direct effects of mediators on bronchial tissue. Although the IgE mediated release of mediators from sensitized mast cells seems to play a role in pathogenesis in some individuals for some of the time, there is now increasing awareness that mast cells are also triggered by a number of non-immunological stimuli such as exercise/cold air, infection and agents which activate the complement system. Mast cell mediators are either pre-formed within granules or generated from membrane-bound phospholipids. The pre-formed mediators include histamine, various chemotactic peptides including ECF-A and the high molecular weight neutrophil chemotactic factor (NCF), proteases, glycosidases, and the heparin proteoglycan. The membrane-derived agents include the lipoxygenase products (e.g. LTB4 and the "SRS-A" leukotrienes-LTC4/D4/E4), prostaglandins and thromboxane in addition to the PAF-ace-tether (AGEPC). The mediators are diverse both in chemical composition and modes of actions. However, many of the pathological features of bronchial asthma can be explained on the basis of their recognised actions. These can be summarised as follows. Bronchial smooth muscle constriction (histamine, LTC4, LTD4, LTE4, PGF2 alfa, PGD2 and PAF); mucosal oedema (increased permeability--histamine, LTC4, LTD4 and PAF; vasodilation--PGD2, PGE2); mucous plugging (histamine, mono-HETEs and LTC4); inflammatory cell infiltrate (NCF, ECF-A peptides, HETEs, LTB4 and PAF); desquamation of epithelium (proteases, glycosidases, together with lysosomal enzymes, and basic proteins derived from neutrophils and eosinophils). It is likely that mild, easily reversible, episodic asthma is due largely to bronchial smooth muscle contraction whereas the late sustained response is more indicative of an inflammatory response, and dependent on the infiltration of neutrophils and eosinophils as the result of mediators which recruit and activate leucocytes. Much of the evidence for this is based on the demonstration that NCF concentrations in the serum are elevated during early and late phase, antigen- and exercise-induced asthma. Moderate to severe asthma is likely to be largely dependent on a subacute/chronic inflammation of the bronchi with eosinophils and mononuclear cells being prominent.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mediators of hypersensitivity and inflammatory cells in the pathogenesis of bronchial asthma. 641 59

To study cytokine regulation of the 5-lipoxygenase (5-LO)/leukotriene (LT) synthase pathway we have developed mouse bone marrow-derived mast cells (BMMC) that minimally express each protein of the pathway by using a novel culture system, lacking interleukin (IL)-3. When mouse bone marrow cells were cultured for 5 weeks with 100 ng/ml c-kit ligand (KL) and 10 units/ml IL-10, a population of > 95% mast cells was obtained. These cells generated 8.3 +/- 4.5 ng of LTC4/10(6) cells and 8.1 +/- 2.4 ng of prostaglandin (PG) D2/10(6) cells after IgE-dependent activation. When these BMMC were cultured for 2-5 weeks more with 100 units/ml IL-3 in the continued presence of KL and IL-10, the IgE-dependent generation of LTC4 and PGD2 increased to 212 +/- 36 and 25.5 +/- 8.6 ng/10(6) cells, respectively. The dramatic increase in the IgE-dependent generation of LTC4 in response to IL-3 was accompanied by a concomitant increase in expression of 5-LO and 5-LO-activating protein and preceded the increased expression of cytosolic phospholipase A2 and LTC4 synthase. The recognition that IL-3 up-regulates the expression of each protein of the 5-LO pathway for the generation of LTC4 contrasts with our recent finding that KL up-regulates the expression of cytosolic phospholipase A2, prostaglandin endoperoxide synthase-1, and hematopoietic PGD2 synthase and increases the IgE-dependent generation of PGD2 in BMMC developed from bone marrow with IL-3. Thus, developmentally segregated regulation of the prostanoid and cysteinyl leukotriene pathways in lineage-related committed mast cell progenitors reveals the pleiotropism of this effector cell of allergic inflammation, a cytokine/growth factor basis for preferential expression of pathways of eicosanoid biosynthesis, and the particular role of IL-3 in regulating the expression of the proteins of the 5-LO/LTC4 synthase pathway.
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PMID:Interleukin-3 regulates development of the 5-lipoxygenase/leukotriene C4 synthase pathway in mouse mast cells. 755 81

H1-blockers may have antiallergic properties which cause the blocking of eicosanoid release, and the effect of these drugs may differ according to the phenotype of mast cells. This study examined the ability of terfenadine and cetirizine to inhibit the release of arachidonic acid-derived mediators from human lung and colon cells. Dispersed cells were challenged with anti-IgE in the presence or absence of 10 microM of terfenadine or cetirizine, and the release of prostaglandin (PG)D2 and leukotriene (LT)C4/D4 was assessed by enzyme immunoassay (EIA). Terfenadine caused significant inhibition of both PGD2 and LTC4/D4 (49 +/- 9 and 29 +/- 19%, respectively) from human lung cells but had a less marked effect on PGD2 release from human colon cells (21 +/- 9% for PGD2 and 18 +/- 9% for LTC4/D4). In contrast, although cetirizine caused significant inhibition of both mediators measured in lung cells (38 +/- 16% for PGD2 and 34 +/- 19% for LTC4), it did not cause any significant inhibition of either mediator from human colon cells. These findings suggest that H1-antagonists may have additional properties, and the differential effects of cetirizine on lung and colon tissue may indicate differences in mast cell phenotype.
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PMID:Pharmacologic heterogeneity of human lung and colon cells: effect of terfenadine and cetirizine. 757 21

Metabolism of arachidonic acid was studied in the unique human mast cell line HMC-1. By HPLC and/or gas chromatography mass spectrometry (GC-MS), 19 oxygenated metabolites were identified, including monohydroxy acids, leukotrienes, prostaglandins, and thromboxane. Intact cells incubated with the calcium ionophore A23187 and arachidonic acid expressed 5-lipoxygenase activity and produced 5-hydroxyeicosatetraenoic acid (5-HETE) as the major metabolite (745 pmol/10(7) cells) followed by leukotriene (LT) C4 (245 pmol/10(7) cells) and 11-trans-LTC4 (74 pmol/10(7) cells). Low but clearly detectable levels of LTB4 were also observed. The total amounts of 5-LO products were comparable to those obtained with RBL-1 cells and corresponded to approx. 30% of the levels obtained with isolated human polymorphonuclear leukocytes. Time-course experiments revealed that HMC-1 cells contained the enzyme activities required to metabolize LTC4 into LTD4 and further into LTE4. The profile of prostanoids included, prostaglandin (PG) E2, PGF2 alpha, and PGD2, whereas 6-keto-PGF1 alpha, reflecting prostacyclin formation, could not be detected. Furthermore, we were able to unambiguously establish that HMC-1 cells could produce substantial amounts of thromboxane (TX) A2, measured as TXB2 (0.1-2.2 nmol/10(7) cells). Generation of TXA2 in such quantities, exceeding those of LTC4, suggests that mast cells may be an important source of thromboxane and points to a possible role for these cells in hemostasis and thrombosis. After approx. 10 passages in culture, 5-lipoxygenase activity in HMC-1 cells drastically declined concomitantly with changes in growth behavior and cell morphology. Analysis by Northern and Western blots revealed that loss of 5-lipoxygenase activity correlated well with a reduced 5-lipoxygenase gene expression at both a transcriptional and translational level. This loss of enzyme activity and gene expression may be related to a genetic abnormality propagated in HMC-1 cells, i.e., a 10;16 translocation, which thus involves the chromosome containing the 5-lipoxygenase gene.
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PMID:Arachidonic acid metabolism in the human mast cell line HMC-1: 5-lipoxygenase gene expression and biosynthesis of thromboxane. 759 81


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