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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysophosphatidylcholine (lyso-PC), a natural product of phospholipase A2 activity, induced the secretion of both granule-associated beta-hexosaminidase and newly generated leukotriene C4 from mouse bone marrow-derived mast cells. Micromolar concentrations of lyso-PC potentiated the release of beta-hexosaminidase induced by specific antigen but not the calcium ionophore, A23187. Exogenous adenosine was relatively ineffective in enhancing beta-hexosaminidase release from cells challenged with lyso PC. Lyso-PC caused a marked increase in intracellular free-calcium levels and induced the activation of protein kinase C (PKC). These effects could not be abrogated by a prolonged preincubation with pertussis toxin. Staurosporine, an inhibitor of PKC, partially inhibited the abilities of antigen and A23187 to induce beta-hexosaminidase release but was ineffective when lyso-PC was the secretagogue. Lyso-PC appears to activate mast cell PKC, but its ability to stimulate mast cell mediator release appears to be related to its ability to elevate intracellular free calcium concentrations.
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PMID:Lysophosphatidylcholine induces mast cell secretion and protein kinase C activation. 183 66

The hematopoietic growth factor IL-3 promotes the proliferation and development of several hematopoietic lineages. Inasmuch as protein kinase C has been suggested to mediate the response of IL-3, we examined the accumulation of diradylglycerols (DG) in response to IL-3 in CFTL-12 cells, a murine mast cell line that requires IL-3 for growth. Exposure of CFTL-12 cells to IL-3 resulted in the conversion of [3H]myristate-labeled lipids to DG. Mass analysis of the DG of CFTL-12 cells cultured in the presence of IL-3 showed that 58% was the ether-linked form, alkylacylglycerol, and 42% was diacylglycerol. The levels of both alkylacylglycerol and diacylglycerol declined when CFTL-12 cells were withdrawn from IL-3 and became quiescent. Stimulation of quiescent cells with IL-3 produced an acute increase in the mass of both alkylacylglycerol and diacylglycerol, consistent with phosphatidylcholine as a significant source. The effects of PMA on the generation of DG were examined to explore the role of protein kinase C activation in the response to IL-3. PMA stimulated an increase in DG accumulation that was not augmented by the simultaneous addition of IL-3. Down-modulation of protein kinase C by long term PMA treatment reduced, but did not eliminate, the IL-3-stimulated increase in DG, suggesting that protein kinase C activation results in an amplification of the initial accumulation of DG. These results indicate a role for DG, generated through the hydrolysis of phosphatidylcholine, in the induction of protein kinase C activity and the events leading to cell proliferation in response to IL-3.
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PMID:IL-3-induced generation of alkylacylglycerol and diacylglycerol in an IL-3-dependent cell line. 191 82

Rat mast cells purified on a Percoll gradient were challenged with compound 48/80 and protein kinase C activity in the cell pellets and the amount of histamine release into the supernatant was assayed by measuring the incorporation of 32P from [gamma 32P]ATP (adenosine triphosphate) into lysine-rich histone and by the fluorometric technique, respectively. In another series of experiments, rat mast cell granules were isolated in a gradient from sonicated rat mast cells and diphosphoinositide kinase activity was assayed by measuring the incorporation of 32P from [gamma 32P]ATP into triphosphoinositide on oxalic acid-impregnated silica gel plates after the extraction of lipids in acidic condition. Azelastine (A-5610, E-0659) inhibited the histamine release from the cells in parallel with the tendency to inhibit the increased protein kinase C activity in the activated mast cells. Azelastine also inhibited the diphosphoinositide kinase activity in the granules. These inhibitory effects of azelastine on the phosphorylation enzymes in rat mast cells may be involved in the inhibitory mechanism of the mediator release from the cells.
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PMID:Inhibitory effects of azelastine on protein kinase C and diphosphoinositide kinase in rat mast cells. 197 Jul 35

Infection of the bone marrow-derived mast cell line PB-3c with a retrovirus carrying oncogenic c-Ha-ras or v-Ha-ras reduced the interleukin 3 (IL-3) growth requirement and induced a state of tumorigenicity. In contrast, normal c-Ha-ras had no effect on the IL-3 requirement of this cell line nor did the cells become tumorigenic. A factor reduction similar to that caused by activated Ha-ras was transiently obtained with 12-O-tetradecanoylphorbol-13-acetate in the PB-3c cells expressing normal c-Ha-ras. The analogous stimulation of protein kinase C (PKC) in PB-3c cells producing oncogenic Ha-ras led to an additional reduction of the IL-3 requirement during the first 24 h. In the absence of IL-3, the prolonged exposure of the cells to 12-O-tetradecanoylphorbol-13-acetate for 72 h resulted in a stimulation of growth when activated but not when normal Ha-ras was expressed. PB-3c cell lines expressing activated Ha-ras neither revealed differences in the amounts nor in the subcellular distribution of PKC activity but displayed elevated levels of immunoreactive beta-PKC compared to the parental PB-3c cells. Upon 12-O-tetradecanoylphorbol-13-acetate treatment, a protracted down-regulation of the immunodetectable alpha-PKC as well as constitutively high levels of c-fos mRNA were observed when oncogenic Ha-ras was expressed. These data suggest the involvement of specific PKC subtypes and of c-fos in the reduction of the IL-3 requirement caused by activated Ha-ras in this particular hematopoietic cell line.
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PMID:Tumor-promoting phorbol ester and activated Ha-ras synergistically reduce the interleukin 3 requirement in a mast cell line. 198 80

Interleukin 3 (IL-3) is transiently produced by murine bone marrow-derived mast cells in response to antigen stimulation of the high-affinity immunoglobulin E receptors. We have studied the postreceptor signaling pathways involved in regulating expression of the IL-3 gene in the murine mast cell line PB-3c. Large amounts of IL-3 mRNA accumulated after exposure of cells to calcium ionophore A23187, a reagent that increases intracellular Ca2+. Phorbol 12-myristate 13-acetate, which stimulates protein kinase C, did not induce IL-3 mRNA accumulation, although it did potentiate the effect of A23187. Nuclear run-on analysis showed that the IL-3 gene is constitutively transcribed in unstimulated cells and that treatment with A23187 and/or phorbol ester has no influence on its transcription rate. The effect of A23187 was found to be due to stabilization of the IL-3 mRNA. In cells maintained in the presence of A23187 the IL-3 mRNA was stable during 3 hr of incubation with actinomycin D, whereas removal of A23187 under the same conditions resulted in rapid degradation of the mRNA. These results indicate that control of expression of the IL-3 gene in mast cells is primarily at the posttranscriptional level and that the Ca2(+)-dependent signal-transduction pathway plays an important role in this process. Synthesis of granulocyte/macrophage colony-stimulating factor mRNA in response to A23187 and phorbol ester was found to be subject to both transcriptional and posttranscriptional regulation.
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PMID:Regulation of interleukin 3 mRNA expression in mast cells occurs at the posttranscriptional level and is mediated by calcium ions. 210 89

The acute incubation of mouse bone marrow-derived mast cells with low concentrations of agents known to activate protein kinase C [phorbol myristate acetate (PMA), 1,2-dioctanoyl-sn-glycerol (diC8), and 1-oleoyl-2-acetyl-glycerol (OAG)] caused an enhancement of beta-hexosaminidase release stimulated by the calcium ionophore A23187. Higher concentrations of protein kinase C activators tended to inhibit A23187- or antigen-induced preformed mediator release. All concentrations studied induced a striking mast cell hyporesponsiveness to the mediator release augmenting effect of adenosine. Agents that have been reported to block protein kinase C activity [1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride (H-7) and sphingosine] demonstrated diverse responses in this system. Up to 100 microM H-7 failed to affect mast cell beta-hexosaminidase release in the presence or absence of PMA and secretagogue. Sphingosine (10 microM) was a potent inhibitor of antigen- or A23187-induced mediator release as well as adenosine responsiveness. Sphingosine also blocked the effects of PMA noted above in a dose-dependent fashion. The generation of leukotriene C4 (LTC4) by stimulated mast cells surprisingly was not affected by concentrations of diC8 that significantly inhibited granule-associated mediator release. Translocation of protein kinase C activity from the cytosol to the mast cell membrane was evident in cells briefly pretreated with A23187, adenosine alone, and diC8 in the presence of Tyrode's buffer, A23187, or adenosine. These findings lend further support to the contention that signal transduction from mast cell adenosine receptors to processes that regulate degranulation may involve protein kinase C.
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PMID:Modulation of mast cell responses to adenosine by agents that alter protein kinase C activity. 214 Dec 57

We have reported that mast cells adhere to laminin after activation with PMA. In this study, we demonstrate that the cross-linking of cell surface high-affinity IgE-R on mast cells derived from mouse bone marrow cultured for 3 wk in the presence of WEHI-3-conditioned media acts as a highly sensitive physiologic stimulus for this attachment and that receptor activation is also induced by calcium ionophore A23187. Adherence occurred at threefold log concentrations less of A23187 and Ag than required for histamine release in a selective subpopulation comprising 20 to 30% of the total cells. At higher concentrations of agonist that permitted histamine release, the time course for degranulation was shown to be more rapid than that of adherence. Adherence was inhibited by antibodies to laminin and laminin receptor and was calcium ion and temperature dependent. Treatment of cells with dibutyryl cAMP, which activates protein kinase A, inhibited both adherence and histamine release induced by Ag or calcium ionophore. Treatment of cells with staurosporin, which inhibits protein kinase C, also inhibited adherence and histamine release induced by calcium ionophore, but was not significantly active against either adherence or histamine release induced by Ag. It thus appears that agents which modulate intracellular signaling mechanisms are equally effective toward histamine release and adherence, suggesting these two events are intimately linked in stimulus secretion coupling. Specific cytokines stimulating mast cell adhesion to laminin could not be found; however, culture of mast cells with TGF-beta 1 was determined to enhance IgE-mediated adherence to laminin. Hence, the high-affinity IgE-R on the mast cell functions not only in exocytosis but also facilitates the process of mast cell adherence to laminin.
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PMID:Regulation of adhesion of mouse bone marrow-derived mast cells to laminin. 214 20

In order to delineate structural-functional relationships of the mast cell receptor for IgE (Fc epsilon RI) by molecular-genetic analysis, a transfectable cell must be identified which resembles mast cells except for being deficient in receptors. We have found that the well known murine mastocytoma P815 is suitable. These cells express no Fc epsilon RI, lack mRNA for the alpha and beta subunits of the receptor, but contain some mRNA for gamma chains. After transfection with the cDNA for each of the subunits, stable clones could be isolated which expressed several hundred thousand normal Fc epsilon RI and synthesized large amounts of mRNA for alpha, beta, and gamma, the last at 3-fold higher levels than in the untransfected cells. Aggregation of the transfected receptors led to opening of presumptive calcium channels and to activation of phospholipase C, phospholipase A2, and protein kinase C. The kinetics and other characteristics of the signals were similar to those observed after stimulation of the rat tumor mast cells from which the receptor genetic material had been derived but were smaller in magnitude. These weaker signals most likely result from an overall reduced reactivity exhibited by the P815 cells since stimulation by other ligands led to weaker or even no responses. The cells failed to degranulate after either receptor aggregation or reaction with ionophores with or without phorbol ester. Both the transfected and untransfected P815 cells express Fc receptors for IgG (Fc gamma RII) which, interestingly, independently triggered similar responses despite their apparently simpler subunit structure.
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PMID:Transmembrane signaling in P815 mastocytoma cells by transfected IgE receptors. 216 65

Interleukin 3 (IL-3) is required for the survival and proliferation of mouse bone marrow derived mast cells (BMMC). Although interleukin 4 (IL-4) has no direct effect on growth activity, it synergizes with IL-3 in promoting the growth of these cells. The intracellular mechanism by which these ligand-receptor interactions promote mast cell growth are not well documented in the literature. Here we present evidence that both IL-3 and IL-4 have been found to activate protein kinase C (PKC) and phosphatidylinositol turnover in BMMC, in a similar time- and dose-dependent manner, indicating that activation of PKC is not sufficient to induce proliferation in these cells. In this work we addressed the question as to whether the activation of PKC is necessary for mast cell proliferation. Activation of PKC by phorbol myristate acetate causes inhibition of IL-3-mediated growth for the first 72 h of incubation. The inhibition in IL-3-mediated proliferation gradually lessens with the stages of PKC depletion, which is complete after 72 h. The enhancement in phorbol myristate acetate-treated cells grows as PKC is depleted. The inactive phorbol ester, 4-alpha-phorbol, had no effect on proliferation of BMMC. Cells, PKC-depleted by chronical phorbol ester treatment, responded to IL-3 or IL-4 with a significant increase in [3H] thymidine uptake over PKC containing cells stimulated with the same lymphokine. Use of antibodies to these lymphokines showed that the enhanced response of the PKC-depleted BMMC was not due to the additional autocrine production of IL-3 or IL-4 by these cells. The PKC-depleted cells retain the capacity to return to almost normal levels of PKC activity and sensitivity to IL-3 and IL-4, after 72 and 120 h, respectively. These results indicate that PKC plays an important inhibitory role in IL-3- and IL-4-mediated proliferation of BMMC.
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PMID:Protein kinase C plays an inhibitory role in interleukin 3- and interleukin 4-mediated mast cell proliferation. 226 15

A role for second messenger-regulated protein kinases in the early post-IL-3 receptor signal transduction pathway was investigated in the mast cell/megakaryocyte line R6-XE.4. The activity of the calcium- and phospholipid-dependent protein kinase C (PKC) was assessed by the ability of the enzyme to phosphorylate histone H1 in the presence of calcium, diacylglycerol, and phosphatidylserine or after proteolytic activation of PKC with trypsin. In high serum-supplemented cells, but not in cells that were preincubated in serum-deficient media for 6 h, subsequent treatment for 15 min with synthetic IL-3 (10 micrograms/ml) caused up to a sixfold increase in the calcium- and lipid-stimulated histone H1 phosphorylating activity of particulate-associated PKC after fractionation on MonoQ. However, there was no corresponding reduction of cytosolic PKC activity. Therefore, IL-3 appeared to modify the activity of preexisting membrane-associated PKC rather than eliciting its recruitment from the cytoplasm in R6-XE.4 cells. This was in contrast to the situation with FDC-P1 cells, where IL-3 induced PKC translocation. IL-3 also stimulated a cytosolic protein kinase that phosphorylated a synthetic peptide patterned after a phosphorylation site in ribosomal protein S6, but this IL did not alter the activity of cAMP-dependent protein kinase.
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PMID:IL-3-induced activation of protein kinases in the mast cell/megakaryocyte R6-XE.4 line. 230 40


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