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 participate in the host defense against parasites. Mast cells release leukotrienes (LTs), potent 5-lipoxygenase (LO) products of arachidonic acid well-known to be involved in the inflammatory process. After incubation with Toxoplasma gondii, mast cells were found to degranulate and release LTB4; this interaction damages the tachyzoites. This mast cell activity against the tachyzoites was inhibited by the 5-LO inhibitor A-63162 and the 5-LO-activating protein inhibitor MK-886 but not by the cyclooxygenase inhibitor indomethacin. Reactive oxygen species were not implicated in the mast cell-mediated toxoplasmacidal activity. The generation of LTs is important for mast cell secretion, and LTB4 released by mast cells and other inflammatory cells may be a key factor in the host defense against T. gondii.
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PMID:The importance of leukotrienes in mast cell-mediated Toxoplasma gondii cytotoxicity. 959 43

In addition to its neuronal effects, nerve growth factor (NGF) is known to act on inflammatory and immune cells. The aim of the present study was to investigate the effect of colchicine on NGF-induced leukocyte accumulation and thermal hyperalgesia. Initial experiments showed that intradermal injection of recombinant human (rh) NGF (0.8 and 4 microg) caused a longlasting increase in tissue myeloperoxidase (MPO) indicating leukotactic activity of NGF. Colchicine (0.3 and 1 mg/kg) attenuated the NGF (0.8 and 4 microg)-induced increase in tissue myeloperoxidase (MPO) as determined 6 h after NGF application. Intraplantar injection of NGF into the rat hindpaw caused a decrease in thermal nociceptive threshold, which, at 4 microg NGF, was accompanied by moderate (about 35% increase in paw volume) edema. The thermal hyperalgesia was evident 20 min after injection and lasted less than 4 h. Colchicine (0.3 and 1 mg/kg) had no significant effect on NGF-induced edema, but reduced NGF-induced thermal hyperalgesia. Colchicine (1 mg/kg) did not significantly reduce thermal hyperalgesia produced by intraplantar bradykinin, prostaglandin E1, or 5-hydroxytryptamine. Treatment of rats with a dose of indometacin (2 mg/kg) that was sufficient to block cyclooxygenase had no significant effect on NGF-induced thermal hyperalgesia or edema. In vitro, colchicine (0.4-12 microg/ml) did not significantly influence NGF (10 ng/ml)-induced histamine release from rat peritoneal cells, suggesting that a mast cell stabilizing effect of colchicine did not contribute to inhibition of NGF-induced thermal hyperalgesia. The results show that NGF causes localized indometacin-resistant thermal hyperalgesia that can be blocked by the microtubule disrupting agent colchicine. These results raise the possibility that a mechanism by which NGF produces peripheral sensitization is related to its leukotactic effect.
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PMID:Effect of colchicine on nerve growth factor-induced leukocyte accumulation and thermal hyperalgesia in the rat. 975 13

Prostaglandins likewise leukotriens are proinflammatory mediators resulting from metabolic degradation of the arachidonic acid originating from membrane phospholipids. The most important products of enzyme cyclooxygenation of arachidonic acid are prostaglandins D2, E2, F2a, tromboxane A2 and prostacyclin. Prostaglandins express their tissue effects via the five basic receptor types. Within the allergic inflammation activated mast cell synthesizes prostaglandin D2 (first lipid mediator) which has bronchoconstrictive and vasodilating effects and attracts neutrophilic leukocytes. Moreover, it also participates in the late phase reactions, six hours subsequent to the exposure to the allergen. This mediator is also important in pathogenesis of urticaria, allergic rhinitis and allergic bronchial asthma. In addition to prostaglandin D2, prostaglandin F2a and tromboxane A2 also have bronchoconstrictive actions, while prostacyclin and prostaglandin E have bronchodilating effects. Inhalation of prostaglandin E prevents asthmatic attacks caused by allergens, strain, metabisulfite and ameliorates attacks of aspirin asthma, which confirms the hypothesis that aspirin asthma is based on cyclooxigenase inhibition and increased leukotriene production. In patients with atopic dermatitis, prostaglandin E has suppressive effects on Interferon gamma production by Th1 helper cells and increases production of Interleukin 4 by the Th2 cells. Tromboxane A2 plays a certain role in the development of bronchial hyperreactivity and late asthmatic response. Prostaglandins are also important mediators in the pathogenesis of allergic conjunctivitis. Most of nonsteroidal antiinflammatory drugs inhibit the enzyme cyclooxygenase and thus also prostaglandin biosynthesis and release.
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PMID:[The role of prostaglandins in allergic inflammation]. 986 13

We examined the mechanisms of quinolone phototoxicity in vivo and in vitro. Simultaneous p.o. administration of a quinolone and ultraviolet-A (UVA) irradiation for 4 h induced auricular skin inflammation in BALB/c mice, including edema and neutrophil infiltration in the dermis. Antioxidants inhibited the inflammation in the early stage and cyclooxygenase inhibitors did in both the early and later stages, whereas 5-lipoxygenase inhibitors or histamine antagonists had no effect. The phototoxic inflammation was also induced in mast cell-deficient WBB6F1-W/Wv mice. Corresponding to the in vivo results, incubation with a quinolone under UVA irradiation stimulated BALB/c 3T3 mouse fibroblast cells to release prostaglandin E2 (PGE2) and 6-keto-PGF1alpha, but not leukotriene B4. In contrast, UVA-pre-irradiated quinolones did not affect PG release from fibroblasts. The PGE2 release was inhibited by cyclooxygenase inhibitors, antioxidants, protein kinase C (PKC) inhibitors and a tyrosine kinase (TK) inhibitor, but not by antibodies against tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1). These results lead to a hypothesis that reactive oxygen species generated from quinolones under UVA irradiation trigger PG release from dermal fibroblasts via PKC and TK activation, resulting in skin inflammation and that 5-lipoxygenase products, histamine, TNF alpha or IL-1 is ruled out from the mechanism.
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PMID:Mechanisms of quinolone phototoxicity. 1002 81

Nerve growth factor (NGF) is well recognized to have a number of potent effects on mast cells, including increasing mast cell numbers in vivo and inducing mast cell degranulation in vitro. More recently, NGF has been demonstrated to induce PGD2 production by mast cells through the induction of mast cell cyclooxygenase expression. We have observed that NGF at doses as low as 10 ng/ml will induce IL-6 production and inhibit TNF-alpha release from rat peritoneal mast cells in the presence of lysophosphatidylserine as a cofactor. NGF synergizes with LPS treatment of peritoneal mast cells (PMC) for the induction of IL-6. Examination of the mechanism of this phenomenon has revealed that NGF can induce both rat PMC and mouse bone marrow-derived cultured mast cells to produce substantial levels of PGE2. This response is maximal at later time points 18-24 h after NGF activation. The ability of NGF to induce PGE2 is not dependent on mast cell degranulation. Other stimuli capable of inducing IL-6, such as LPS, do not induce production of this prostanoid. Inhibition of cyclooxygenase activity by PMC using either flurbiprofen or indomethacin inhibited both the NGF-induced PGE2 synthesis and the NGF-induced alterations in TNF-alpha and IL-6 production. These results suggest a role for mast cell-derived prostanoids in the regulation of local inflammatory responses and neuronal degeneration after tissue injury involving induction of NGF production.
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PMID:Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism. 1020 58

Prostaglandin D2 (PGD2) is the major cyclooxygenase metabolite of arachidonic acid released after stimulation of mast cells. Quantification of metabolites of PGD2 can be used as an objective indices of PGD2 production and hence mast cell activation in vivo. The aim of this thesis was to investigate the feasibility of measuring the primary urinary metabolite of PGD2, 9 alpha,11 beta-PGF2 with enzyme immunoassay (EIA). Measurements of 9 alpha,11 beta-PGF2 in urine made by EIA were compared with values obtained by negative ion chemical ionisation gas chromatography-mass spectrometry (NCI GC-MS), the gold standard method. Levels of 9 alpha,11 beta-PGF2, in urine samples measured by NCI GC-MS were consistently lower than those obtained by EIA. NCI GC-MS analysis revealed the presence of two additional dinor compounds, shorter metabolites of 9 alpha,11 beta-PGF2 in the urine. One of the compounds was identical to 9 alpha,11 beta-2,3-dinor-PGF2 which was generated by beta-oxidation of 9 alpha,11 beta-PGF2 and identified by electron impact (EI GC-MS). Thus, urinary 9 alpha,11 beta-PGF2 concentrations measured by EIA represent the sum of three PGD2 metabolites. For convenience sake, the metabolites are collectively referred to as 9 alpha,11 beta-PGF2 in the subsequent studies. A 3-fold increase in the urinary excretion of 9 alpha,11 beta-PGF2 was documented after allergen-induced bronchoconstriction in nine atopic asthmatics. This challenge was considered a positive control since it is unambiguous that mast cell activation occurs during the early phase of allergen-induced airway obstruction. Histamine-induced bronchoconstriction did not result in an increase in the levels of 9 alpha,11 beta-PGF2 demonstrating that PGD2 was not formed as a consequence of the bronchoconstriction per se. Moreover, bronchial challenge with lysine-aspirin in eight aspirin-intolerant asthmatics elicited bronchoconstriction and was accompanied by a significant increase in the urinary excretion of 9 alpha,11 beta-PGF2. Challenge with a higher dose of aspirin produced an even greater increase in 9 alpha,11 beta-PGF2 levels, indicating a dose-dependent release of PGD2 during aspirin-induced bronchoconstriction. The pattern of mediator release during the early (EAR) and late asthmatic response (LAR) to allergen was investigated by subjecting twelve mild atopic asthmatics to allergen challenge. Within one hour of the maximal bronchoconstrictor response, there was a significant increase in the urinary concentrations of the mast cell markers, 9 alpha,11 beta-PGF2 and N tau-methylhistamine, urinary metabolite of histamine, and the end product of the cysteinyl-leukotrienes, leukotriene (LT)E4. Levels of all three mediators were also significantly elevated above baseline during the LAR. Urinary levels of eosinophil protein X (EPX), a marker of eosinophil activation, remained unaltered during both the EAR and LAR. Preliminary evidence suggests a diurnal variation in the urinary excretion of EPX. Increased airway fluid osmolarity in the lower airways as a result of exercise, has been suggested to trigger mast cell activation and subsequent bronchoconstriction in a subset of asthmatics. Twelve subjects with a history of exercise-induced bronchoconstriction (EIB), exercised on a stationary bicycle ergometer for 5 minutes. Seven of the subjects (responders) experienced bronchoconstriction, whereas, the pulmonary function of the remaining five subjects (non-responders) remained stable. The urinary excretion of 9 alpha,11 beta-PGF2 in the responder group increased significantly compared to the non-responders at 30 and 90 minutes after exercise. The urinary excretion of LTE4 and N tau-methylhistamine was not significantly different between the two groups at either time point after exercise, although there was a tendency for elevated levels of N tau-methylhistamine in the responder group. (ABSTRACT TRUNCATED)
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PMID:On the role of PGD2 metabolites as markers of mast cell activation in asthma. 1035 58

We investigated the effect of sodium nitroprusside (SNP), a donor of nitric oxide, on the formation of platelet-activating factor (PAF) and uterine contractility in mouse uterine horns from mice treated with estrogen. Because the major pathway of PAF synthesis is the remodeling pathway in uterine tissue, we evaluated the incorporation of 14C-acetate into PAF-like molecules. Our results showed that SNP (100-300 mumol/L) caused a transient increase in the synthesis of PAF, which remained cell-associated. The addition of SNP (100-300 mumol/L) to a mouse uterine horn in an isolated organ bath preparation evoked a transient increase in contractility, which was inhibited by hemoglobin (2 micrograms/mL), a nitric oxide scavenger, but not by methylene blue (10 mumol/L), a guanylate cyclase inhibitor. The pharmacological characteristics of the contractions evoked by SNP resembled those evoked after mast cell activation, in that they were blocked by ritodrine (a beta 2 adrenergic agonist, 0.1 mumol/L); indomethacin (a cyclooxygenase inhibitor, 10 mumol/L); ketotifen (a mast cell stabilizer, 1.0 mumol/L); cromolyn sodium (a mast cell stabilizer, 100 mumol/L); pyrilamine (an H1 antagonist, 10 mumol/L); and ketanserine (5HT2 antagonist, 0.1 mumol/L). These data demonstrate that nitric oxide generated from SNP stimulated the synthesis of PAF and evoked contractility in uterine horns from mice treated with estrogen. This result suggests the possibility that these tissue conditions might be favorable for the generation of peroxynitrites, possible mediators of both effects. It is also shown that the contractility evoked by the addition of SNP was not due to production of PAF, because its antagonist, WEB 2086 (10-30 mumol/L, a concentration that blocked contractions evoked by PAF 1 nmol/L), had no effect on the SNP-evoked contractions.
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PMID:Nitroprusside stimulates contractility and the synthesis of 14C-acetylated PAF-like substances in estrogen primed-mouse uterine horns. 1036 96

Measurements of the prostaglandin (PGD2) metabolite 9 alpha, 11 beta-PGF2 in unextracted urine performed by enzyme immunoassay (EIA) were compared with values obtained by negative chemical ionisation gas chromatography-mass spectrometry (NCI GC-MS). Values determined by NCI GC-MS were in the same range but consistently lower than those obtained by EIA, suggesting that other endogenous compounds could be contributing to the immunoreactivity. Isoprostanes were generated by autoxidation of arachidonic acid and the 9 alpha, 11 beta-PGF2 antibody demonstrated less than 0.7% crossreactivity to the mix, making it unlikely that isoprostanes in urine interfere with quantification of 9 alpha, 11 beta-PGF2 by EIA. This was further supported by the 70% reduction in immunoreactive material measured in urine after three days treatment in a healthy volunteer with the cyclooxygenase inhibitor ibuprofen. Purification of urine samples by reverse phase high-performance liquid chromatography (HPLC) revealed the presence of two immunoreactive compounds in addition to 9 alpha, 11 beta-PGF2. The compounds were identified as dinor compounds by NCI GC-MS. One of the compounds was identical to 9 alpha, 11 beta-2,3-dinor-PGF2 which was generated by beta-oxidation of 9 alpha, 11 beta-PGF2 and identified by electron impact (EI)-GC-MS. In conclusion, urinary 9 alpha, 11 beta-PGF2 concentrations measured by EIA represent the sum of 9 alpha, 11 beta-PGF2 and two isomers of its dinor metabolite. Thus, the direct EIA is fast, sensitive and sufficiently specific to monitor activation of the PGD2 pathway, thereby providing a valuable clinical tool to assess the status of mast cell activation in vivo.
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PMID:Analyses of prostaglandin D2 metabolites in urine: comparison between enzyme immunoassay and negative ion chemical ionisation gas chromatography-mass spectrometry. 1041 Mar 85

The purpose of this study was to determine the effects of mast cell coculture on human orbital fibroblasts. Thyroid-associated ophthalmopathy is characterized by infiltration of lymphocytes and mast cells and connective tissue activation in the orbit, leading to a disordered accumulation of hyaluronan and intense inflammation. Here, we report that HMC-1, an established human mast cell line, can activate human orbital fibroblasts to produce increased levels of prostaglandin E2 (PGE2) and hyaluronan when cocultured. HMC-1 cells up-regulate, in these fibroblasts, the expression of PG endoperoxide H synthase-2 (EC 1.14.99.1, PGHS-2), the inflammatory cyclooxygenase. This induction, at a pretranslational level, underlies the increase in PGE2 synthesis. The up-regulation can be attenuated with dexamethasone (10 nM), and the increase in PGE2 production can be inhibited by SC 58125, a specific PGHS-2 inhibitor. Moreover, anti-interleukin-4 receptor antibodies can block prostanoid production in the fibroblasts elicited by HMC-1 cells, suggesting that this cytokine might represent a molecular conduit for mast cell/fibroblast cross-talk. HMC-1 cells also increased hyaluronan synthesis, as was evidenced by a 2-fold increase in [3H]glucosamine incorporation into the macromolecule. To our knowledge, these findings are the first demonstrating the ability of mast cells to activate orbital fibroblasts, and the findings suggest a potential role for these cell-cell interactions in the pathogenesis of thyroid-associated ophthalmopathy.
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PMID:HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis. 1043 7

Prostaglandins generated by the phospholipase A2 (PLA2)/cyclooxygenase (COX) pathway are well known to mediate diverse intracellular and extracellular effects that regulate mammalian development, vascular function, renal physiology, parturition, and immune responses to infection or wounding. In immune-mediated diseases and in certain cancers, this pathway is aberrantly up-regulated and excessive prostaglandin production contributes to the pathology. It is now known that there are two isoforms of COX and multiple secreted and intracellular PLA2 enzymes. The use of isoform-specific inhibitors, coupled with antisense and in vivo gene deletion experiments, has identified independent pathways of arachidonic acid metabolism, which are differentially regulated at the levels of gene expression, protein phosphorylation, and cellular localization. There is cross-talk between the pathways at the level of PLA2 and substrate supply to the two isoforms of COX is apparently compartmentalized. Knockout studies have shown that the two COX isoforms play independent roles in immediate and delayed agonist-induced prostaglandin synthesis. Cytosolic PLA2-alpha is essential for both responses. Inducible secreted forms of PLA2 are, as yet, not essential for either response with the exception of the in vitro murine mast cell immediate response and instances of murine macrophage prostaglandin synthesis. These enzymes amplify the delayed response and are likely to modulate the severity of immune-mediated diseases.
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PMID:Functional coupling and differential regulation of the phospholipase A2-cyclooxygenase pathways in inflammation. 1053 5


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