Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat basophilic leukemia (RBL) cells resemble mucosal mast cells (MMC) and develop few secretory granules under normal culture conditions. RBL cells have been used for the study of secretion and for the possible involvement of MMC in food allergies and irritable bowel syndrome (IBS). The flavonoid quercetin is one of very few molecules that inhibit RBL cell proliferation and constitutive histamine release; it also induces synthesis of rat mast cell protease (RMCP) II and accumulation of secretory granules. Even though quercetin is available as a food supplement over the counter, some early studies had indicated it may be carcinogenic. We, therefore, compared the effect of quercetin to that of other flavonoids with similar structure. Flavone, kaempferol, myricetin and morin were investigated for their action on RBL cell secretion of beta-hexosaminidase stimulated by anti-DNP serum and DNP-BSA, as well as on secretory granule development. Quercetin, myricetin and kaempferol inhibited RBL cell secretion significantly only at 10(-4) M. Flavone inhibited secretion at 10(-4), 10(-5) and 10(-6) M; it also maximally induced secretory granule accumulation as evidenced by light and electron microscopy. In contrast, morin which differs structurally only by one extra hydroxyl group had minimal effect. These results indicate that flavone is capable of inhibiting stimulated secretion and inducing secretory granule development at reasonable concentrations.
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PMID:Differential effect of flavonoids on inhibition of secretion and accumulation of secretory granules in rat basophilic leukemia cells. 1040 73

FcepsilonRI signaling in rat basophilic leukemia cells depends on phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase Rac. Here, we studied the functional relationship among PI3-kinase, its effector protein kinase B (PKB), and Rac using inhibitors of PI3-kinase and toxins inhibiting Rac. Wortmannin, an inhibitor of PI3-kinase, blocked FcepsilonRI-mediated tyrosine phosphorylation of phospholipase Cgamma, inositol phosphate formation, calcium mobilization, and secretion of hexosaminidase. Similarly, Clostridium difficile toxin B, which inactivates all Rho GTPases including Rho, Rac and Cdc42, and Clostridium sordellii lethal toxin, which inhibits Rac (possibly Cdc42) but not Rho, blocked these responses. Stimulation of the FcepsilonRI receptor induced a rapid increase in the GTP-bound form of Rac. Whereas toxin B inhibited the Rac activation, PI3-kinase inhibitors (wortmannin and LY294002) had no effect on activation of Rac. In line with this, wortmannin had no effect on tyrosine phosphorylation of the guanine nucleotide exchange factor Vav. Wortmannin, toxin B, and lethal toxin inhibited phosphorylation of PKB on Ser(473). Similarly, translocation of the pleckstrin homology domain of PKB tagged with the green fluorescent protein to the membrane, which was induced by activation of the FcepsilonRI receptor, was blocked by inhibitors of PI3-kinase and Rac inactivation. Our results indicate that in rat basophilic leukemia cells Rac and PI3-kinase regulate PKB and suggest that Rac is functionally located upstream and/or parallel of PI3-kinase/PKB in FcepsilonRI signaling.
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PMID:Rac and phosphatidylinositol 3-kinase regulate the protein kinase B in Fc epsilon RI signaling in RBL 2H3 mast cells. 1116 Feb 4

There are conflicting reports in the literature as to whether palmitoylethanolamide affects the function of mast cell-related cell lines in vitro, in contrast to the well-documented effects of this compound upon mast cell function in vivo. In the present study, we have reinvestigated the effects of palmitoylethanolamide upon antigen-induced release of [3H]serotonin and beta-hexosaminidase from rat basophilic leukemia RBL-2H3 cells and compared these effects with those of 2-arachidonoylglycerol, anandamide and R1-methanandamide. RBL-2H3 cells were sensitized with a monoclonal anti-DNP IgE, after which they were stimulated with antigen (DNP-HSA). Palmitoylethanolamide produced a small, but significant reduction in antigen-stimulated [3H]serotonin release at high concentrations, whereas anandamide was without effect. In contrast, 2-arachidonoylglycerol and methanandamide increased the antigen-stimulated release of both [3H]serotonin and beta-hexosaminidase. It is concluded that in RBL-2H3 cells, these cannabimimetic fatty acid derivatives do not have potent stabilizing effects upon antigen-induced degranulation.
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PMID:Effects of the cannabimimetic fatty acid derivatives 2-arachidonoylglycerol, anandamide, palmitoylethanolamide and methanandamide upon IgE-dependent antigen-induced beta-hexosaminidase, serotonin and TNF alpha release from rat RBL-2H3 basophilic leukaemic cells. 1148 41

There have been very few reports of the effect of pesticides on immediate allergy. In the previous report, the effect of pyrethroid pesticides and organophosphorus pesticides on immediate allergic reaction was investigated. Subsequently, 12 organonitrogen pesticides, 14 carbamate pesticides and 4 other pesticides were investigated for their effects on the enzyme activity of beta-hexosaminidase as an index of chemical mediator release from rat basophilic leukemia cells (RBL-2H3). Two organonitrogen pesticides, bitertanol and pyridaben, and two organotin pesticides, cyhexatin and fenbutatin oxide, were found to promote beta-hexosaminidase release. Bitertanol non-specifically caused the promotion of chemical mediator release, while the release-promotive action of pyridaben was related to IgE antibody and those of cyhexatin and fenbutatin oxide to cell injury. On the other hand, two organonitrogen pesticides, propiconazole and triadimenol, and imazalil showed release-inhibitory action. These data suggested that some pesticides can affect immediate allergy.
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PMID:[Effects of organonitrogen, carbamate pesticides and others on beta-hexosaminidase release from rat basophilic leukemia cells (RBL-2H3)]. 1181 42

Aggregation of high-affinity IgE receptor FcepsilonRI induces sequential activation of nonreceptor-type protein-tyrosine kinases and subsequent tyrosine phosphorylation of cellular proteins, leading to degranulation in mast cells. A hematopoietic cell-specific adaptor protein, 3BP2, that was originally identified as an Abl SH3-binding protein was rapidly tyrosine phosphorylated by the aggregation of FcepsilonRI on rat basophilic leukemia RBL-2H3 cells. Tyrosine phosphorylation of 3BP2 did not depend on calcium influx from external sources. To examine the role of 3BP2 in mast cells, we overexpressed the SH2 domain of 3BP2 in the RBL-2H3 cells. Overexpression of 3BP2-SH2 domain resulted in a suppression of antigen-induced degranulation as assessed by beta-hexosaminidase release. Even though overall tyrosine phosphorylation of cellular protein was not altered, antigen-mediated tyrosine phosphorylation of phospholipase C-gamma (PLC-gamma) and calcium mobilization were significantly suppressed in the cells overexpressing the 3BP2-SH2 domain. Furthermore, antigen stimulation induced the association of 3BP2-SH2 domain with LAT and other signaling molecule complexes in the RBL-2H3 cells. FcepsilonRI-mediated phosphorylation of JNK and ERK was not affected by the overexpression of 3BP2-SH2 domain. These data indicate that 3BP2 functions to positively regulate the FcepsilonRI-mediated tyrosine phosphorylation of PLC-gamma and thereby the signals leading to degranulation.
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PMID:Regulation of FcepsilonRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells. 1220 Mar 78

Asthma is a complex condition in which exposure to environmental antigens induces inflammatory reactions in the airway characterized by activation of mast cells and eosinophils. Mast cells are known to be the main effector cells in eliciting IgE-mediated allergic response. These cells secrete various substances that perpetuate inflammation and provoke airway smooth muscle (ASM) contraction. A newly recognized addition to the repertoire of FcepsilonRI-mediated signaling events is the activation of sphingosine kinase leading to the generation of the potent sphingolipid mediator, sphingosine-1-phosphate (S1P) from sphingosine. S1P secretion by the lung significantly increases after challenge with an allergen, adding this sphingolipid metabolite to the variety of mediators that are released during an allergic reaction [FASEB J. 15 (2001) 1212]. Indeed, similar to previous reports, we found that FcepsilonRI cross-linking not only increased cellular levels of S1P, it also markedly enhanced its secretion from rat basophilic leukemia RBL-2H3 cells. Moreover, S1P induced degranulation of RBL and bone marrow derived mast cells (BMMCs) cells as determined by hexosaminidase release. Treatment of BMMCs with the sphingosine kinase inhibitors, DL-threo-dihydrosphingosine and dimethylsphingosine, reduced IgE/Ag stimulated histamine release. RT-PCR analysis demonstrated that these mast cells express S1P receptors EDG-1 and EDG-5 but not EDG-3, EDG-6 or EDG-8 transcripts. Further studies are needed to determine whether IgE triggering results in transactivation of EDG-1 or EDG-5 present on mast cells and whether this is a critical event for mast cell activation.
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PMID:The roles of sphingosine-1-phosphate in asthma. 1221 90

Leukotriene B(4) (LTB(4)) is a potent lipid mediator involved in host defense and inflammatory responses. It causes chemotaxis, generation of reactive oxygen species, and degranulation. However, only little is known of the molecular mechanisms by which LTB(4) induces these biological activities. To analyze the intracellular signaling pathways to mediate lysosomal enzyme release through the cloned LTB(4) receptor (BLT1), we transfected BLT1 to rat basophilic leukemia cells (RBL-2H3). LTB(4) dose-dependently released beta-hexosaminidase, and the release was mostly inhibited when the cells were pretreated with pertussis toxin, indicating that the degranulation is mediated by G(i) proteins. LTB(4) activated phosphatidylinositol 3-kinase (PI3-K) through G(i), and inhibition of PI3-K by wortmannin or LY290042 inhibited degranulation. Granulocytes from PI3-Kgamma-deficient mice showed reduced LTB(4)-induced degranulation, suggesting that this isozyme of PI3-K is involved in the degranulation. LTB(4) also caused calcium release from intracellular stores and calcium influx from the outside milieu through G(i), but only the calcium influx is critical for the lysosomal enzyme release. Calcium influx and PI3-K activation are both downstream events of G(i), since they were inhibited by pertussis toxin. These two events are in essence independent each other, because calcium depletion did not affect PI3-K, and inhibition of PI3-K did not attenuate calcium influx significantly. Thus, our results have clearly shown that LTB(4) binds BLT1 and activates G(i)-like protein, and both PI3-Kgamma activation and a sustained calcium elevation by calcium influx are necessary for enzyme release in these cells.
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PMID:Requirement of phosphatidylinositol 3-kinase activation and calcium influx for leukotriene B4-induced enzyme release. 1224 16

Early endosomes and a perinuclear, Rab-11-positive compartment have been implicated in the recycling of internalized receptors. In this study, we show that synaptotagmin III (Syt III), a member of the Syt family of proteins, is required for the formation and delivery of cargo to the perinuclear endocytic recycling compartment (ERC). We demonstrate that rat basophilic leukemia (RBL-2H3) mast cells endogenously express Syt III, and >70% of this protein colocalizes with early endosomal markers, such as EEA1, annexin II and syntaxin 7, and the remaining protein colocalizes with secretory granule (SG) markers such as beta-hexosaminidase, histamine and serotonin. To study the functional role of Syt III, we stably transfected RBL cells with Syt III antisense cDNA and monitored the route of transferrin (Tfn) internalization in cells that displayed substantially reduced (<90%) levels of Syt III (RBL-Syt III(-)). In these cells, Tfn binding and internalization into early endosomes were unaltered. However, whereas in the mock-transfected cells Tfn was subsequently delivered to the ERC, in the RBL-Syt III(-) cells, Tfn remained associated with dispersed peripheral vesicles and Rab 11 remained cytosolic. Nevertheless, the rates of Tfn internalization and recycling were not affected. RBL-Syt III(-) cells also displayed enlarged SGs, reminiscent of the SGs present in Chediak-Higashi (beige) mice. However, morphometric analyses suggested that granule formation was unaltered and that the calculated unit granule volume is the same in both cell lines. Therefore, our results implicate Syt III as a critical factor for the generation and delivery of internalized cargo to the perinuclear endocytic recycling compartment and suggest a possible link between ERC and recycling from immature SGs during the process of SG maturation.
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PMID:Synaptotagmin III is a critical factor for the formation of the perinuclear endocytic recycling compartment and determination of secretory granules size. 1245 24

We transfected the alpha-chain of human FcepsilonRI into rat basophilic leukemia cell line RBL-2H3, established several stable transfected cells, and screened them by beta-hexosaminidase release induced by sensitization with human IgE and stimulation with anti-human IgE antibody. A cloned cell line RBL-hEIa-2B12 was the strongest responder among the transfected cell clones. The concentrations of cytosolic free Ca2+ concentration in the human IgE-sensitized cells increased after stimulation with anti-human IgE antibody. Thus, it is suggested that the alpha-chain of human FcepsilonRI is associated with the beta-chain and/or gamma-chain of rat FcepsilonRI, and that they form functional high affinity IgE receptor complexes. The total IgE concentrations of the sera from allergic patients were determined by using the beta-hexosaminidase release assay, where the transfected cells were sensitized with diluted and heat-inactivated (at 56 degrees C for 30 min) serum and stimulated with anti-human IgE antibody. The IgE concentration obtained correlated with those measured by an enzyme immunoassay method. beta-Hexosaminidase release induced by stimulation with 5 times diluted serum was sometimes less than the release induced by the same serum; diluted 25 times or 125 times, suggesting that these serum contained factors that blocked IgE binding to FcepsilonRI or cross-linking by anti-human IgE antibody. The results suggested that our system will be useful for detecting FcepsilonRIalpha-bindable IgE in human serum.
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PMID:Application of human Fc epsilon RI alpha-chain-transfected RBL-2H3 cells for estimation of active serum IgE. 1257 89

Two novel stem cell factor (SCF) dependent human mast cell lines, designated LAD 1 and 2, were established from bone marrow aspirates from a patient with mast cell sarcoma/leukemia. LAD 1 and 2 cells have the ultrastructural features of human mast cells, and express FcepsilonRI, CD4, 9, 13, 14, 22, 31, 32, 45, 64, 71, 103, 117, 132, CXCR4 (CD184), CCR5 (CD195); and intracytoplasmic histamine, tryptase and chymase. LAD 1 and 2 do not exhibit activating mutations at codon 816 of c-kit. Both LAD 1 and 2 release beta-hexosaminidase following FcepsilonRI or FcgammaRI aggregation. The availability of these cell lines offers an unparalleled circumstance to examine the biology of human mast cells.
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PMID:Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcepsilonRI or FcgammaRI. 1280 24


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