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

Recent evidence suggests that tyrosine kinases play an important role in signal transduction mechanisms utilized by a range of different agonists in many cell types. We have investigated the effects of four different inhibitors of tyrosine kinases on IgE-dependent histamine release from human lung mast cells and basophils. Genistein inhibited the anti-IgE-induced histamine release from human basophils (at 10 microM genistein, inhibition = 55 +/- 5%, n = 17, P < 0.005) with an IC50 of 8 microM, but was much less effective in the human lung mast cell (at 10 microM, inhibition = 18 +/- 6%, n = 11, P < 0.05). Two inactive analogs of genistein, genistin and diadzein, failed to affect anti-IgE-induced histamine release significantly in either mast cells or basophils. A second inhibitor of tyrosine kinases, tyrphostin 25, inhibited IgE-dependent release from basophils (at 10 microM, inhibition = 25 +/- 7%, n = 6, P < 0.05) though it was less effective than genistein and failed to affect IgE-induced histamine release from human lung mast cells (at 10 microM, inhibition = 22 +/- 16%, n = 5, P = NS). In contrast, methyl 2,5 dihydroxycinnamate (MDC) failed to inhibit anti-IgE-dependent histamine release in human basophils (at 10 microM, inhibition = 3 +/- 3%, n = 5, P = NS) but proved to be an effective inhibitor of anti-IgE-induced degranulation in human lung mast cells (at 10 microM, inhibition = 53 +/- 16%, n = 5, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of tyrosine kinases in IgE-mediated signal transduction in human lung mast cells and basophils. 128 Apr 50

Stem cell factor (SCF) or c-kit ligand is a growth factor cytokine produced by stromal cells that is known to influence mast cell proliferation and differentiation. We hypothesized that SCF may also influence the adhesion of mast cells to connective tissue matrix. To examine this hypothesis, we stimulated MCP5/L mast cells or murine bone marrow-derived cultured mast cells (BMCMC) with either SCF or PMA and observed adhesion to fibronectin (FN). As expected, 80 to 90% of PMA-activated MCP5/L cells or BMCMC adhered to FN. In addition, SCF promoted MCP5/L cell or BMCMC adhesion to FN in a dose-response fashion with 50 to 60% of BMCMC adhering to FN at a concentration 10 ng/ml of SCF. BMCMC adhesion was observed with as little as 200 pg/ml of SCF. Adhesion of SCF stimulated BMCMC to FN did not require IL-3, but was dependent on the concentration of FN used to coat the assay surface. Mast cell adhesion in the presence of SCF appeared to occur through an integrin receptor as adhesion was calcium dependent and could be blocked by an RGD (Ang, Gly, Asp)-containing peptide. SCF did not directly mediate adhesion through interaction with c-kit, as FN-coated surfaces exposed to SCF before initiation of the adhesion assay did not promote adhesion in the absence of soluble SCF. Rather, SCF appeared to stimulate adhesion to FN by activating mast cells through its interaction with c-kit. Thus, antibody to SCF blocked adhesion, and rat and murine SCF stimulated BMCMC adhesion to FN, but human SCF, which does not bind to murine c-kit, did not stimulate adhesion. Genistein, which inhibits tyrosine kinase activity, partially inhibited SCF-induced adhesion. SCF thus stimulates mast cell adhesion and, because SCF is produced normally in tissues, it may be a major factor responsible for the adhesion of mast cells to connective tissue matrix under physiologic conditions.
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PMID:Stem cell factor induces mast cell adhesion to fibronectin. 750 10

Both genetic and descriptive studies have implicated the c-kit receptor and its ligand, KL, in the process of oocyte growth in the postnatal mouse ovary. In order to test the hypothesis that KL is an oocyte growth factor, we used an oocyte culture system to study its effects in vitro. Initial experiments established that both ovarian c-kit and KL are biologically active. An immune complex kinase assay demonstrated that ovarian c-kit, found primarily on oocytes, has autophosphorylation activity, and a bone marrow-derived mast cell coculture assay indicated that granulosa cells produce functional KL. The addition of 10 ng/ml KL to growing follicles cultured in collagen gels resulted in a 67% increase in the rate of oocyte growth, and a doubling of the rate was achieved at around 50 ng/ml. ACK2, a monoclonal antibody against c-kit, severely inhibited the growth of late fetal and neonatal oocytes in coculture with ovarian cells and had less effect on growing oocytes cultured in follicles from 10- to 11-day-old mice. Genistein, an inhibitor of tyrosine kinases, including c-kit, blocked oocyte growth and disrupted follicle morphology. In initial studies on the regulation of KL production in granulosa cells, we found that both dibutyryl cyclic AMP and growing oocytes were able to induce increased KL mRNA accumulation in granulosa cell monolayers as assessed by Northern analysis. These studies demonstrate that c-kit and KL are required for maintenance of oocyte growth in vitro.
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PMID:The ligand of the c-kit receptor promotes oocyte growth. 750 47

Mast cells are known to accumulate in various inflammatory processes, some of which are known to be associated with increased local and systemic levels of acute-phase reactants such as serum amyloid A (SAA) or with amyloid deposition. The mechanism(s) by which mast cells are recruited to these sites, however, has not been fully elucidated. It has recently been shown that SAA interacts with extracellular matrix (ECM) components and thereby acts as a chemoattractant and regulator of immune cell migration. On the basis of these observations, we examined the effect of SAA on mast cell adhesion to ECM, an essential step in cellular transmigration. We could first demonstrate strong specific binding of recombinant human SAA (rSAA) to murine mast cells using flow cytometry. Moreover, radiolabeled rSAA was found to bind, in a saturable manner, to mast cells, reaching a binding affinity of 10(-8) M. When immobilized by preincubation with ECM, SAA or its proteolytically degraded amyloid A fragment (amino acid residues 2-82), which contains RGD-related adhesion motif but not the COOH-terminal portion of SAA (amino acid residues 77-104), induced the adhesion of resting mast cells to ECM or laminin. SAA and AA, in soluble or immobilized forms, did not activate mast cells to release mediators. Mast cell adhesion to the immobilized ECM-SAA complex appeared to occur through an integrin recognition, inasmuch as adhesion was calcium dependent and could be blocked by an RGD-containing peptide or by anti-CD29 monoclonal antibody. Genistein also inhibited adhesion, indicating that tyrosine kinase activity was involved. These data suggest that SAA bound to ECM may serve as an important inducer of mast cell adhesion, thus regulating mast cell recruitment and accumulation at these sites, which in turn could potentiate further pathology.
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PMID:Extracellular matrix-anchored serum amyloid A preferentially induces mast cell adhesion. 925 55

1. Inhalation of vanadium compounds, particularly vanadate, is a cause of occupational bronchial asthma. We have now studied the action of vanadate on human isolated bronchus. Vanadate (0.1 microM-3 mM) produced concentration-dependent, well-sustained contraction. Its -logEC50 was 3.74 +/- 0.05 (mean +/- s.e.mean) and its maximal effect was equivalent to 97.5 +/- 4.2% of the response to acetylcholine (ACh, 1 mM). 2. Vanadate (200 microM)-induced contraction of human bronchus was epithelium-independent and was not inhibited by indomethacin (2.8 microM), zileuton (10 microM), a mixture of atropine, mepyramine and phentolamine (each at 1 microM), or by mast cell degranulation with compound 48/80. 3. Vanadate (200 microM)-induced contraction was unaltered by tissue exposure to verapamil or nifedipine (each 1 microM) or to a Ca2+-free, EGTA (0.1 mM)-containing physiological salt solution (PSS). However, tissue incubation with ryanodine (10 microM) in Ca2+-free, EGTA (0.1 mM)-containing PSS reduced vanadate-induced contraction. A series of vanadate challenges was made in tissues exposed to Ca2+-free EGTA (0.1 mM)-containing PSS with the object of depleting intracellular Ca2+ stores. In such tissues cyclopiazonic acid (CPA; 10 microM) prevented Ca2+-induced recovery of vanadate-induced contraction. 4. Tissue incubation in K+-rich (80 mM) PSS, K+-free PSS, or PSS containing ouabain (10 microM) did not alter vanadate (200 microM)-induced contraction. Ouabain (10 microM) abolished the K+-induced relaxation of human bronchus bathed in K+-free PSS. This action was not shared by vanadate (200 microM). The tissue content of Na+ was increased and the tissue content of K+ was decreased by ouabain (10 microM). In contrast, vanadate (200 microM) did not alter the tissue content of these ions. Tissue incubation in a Na+-deficient (25 mM) PSS or in PSS containing amiloride (0.1 mM) markedly inhibited the spasmogenic effect of vanadate (200 microM). 5. Vanadate (200 microM)-induced contractions were markedly reduced by tissue treatment with each of the protein kinase C (PKC) inhibitors H-7 (10 microM), staurosporine (1 microM) and calphostin C (1 microM). Genistein (100 microM), an inhibitor of protein tyrosine kinase, also reduced the response to vanadate. 6 Vanadate (0.1-3 mM) and ACh (1 microM- 3 mM) each increased inositol phosphate accumulation in bronchus. Such responses were unaffected by a Ca2+-free medium either alone or in combination with ryanodine (10 microM). 7. In human cultured tracheal smooth muscle cells, histamine (100 microM) and vanadate (200 microM) each produced a transient increase in intracellular Ca2+ concentration ([Ca2+]i). 8. Intracellular microelectrode recording showed that the contractile effect of vanadate (200 microM) in human bronchus was associated with cellular depolarization. 9. It is concluded that vanadate acts directly on human bronchial smooth muscle, promoting the release of Ca2+ from an intracellular store. The Ca2+ release mechanism involves both the production of inositol phosphate second messengers and inhibition of Ca-ATPase. The activation of PKC plays an important role in mediating vanadate-induced contraction at values of [Ca2+]i that are close to basal.
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PMID:The spasmogenic effects of vanadate in human isolated bronchus. 925 12

The present study was conducted to examine the effects of two protein tyrosine kinase inhibitors, genistein and tyrphostin 47, on an in vitro model of allergic asthma. Guinea pigs were sensitized with purified IgG raised against ovalbumin (OA). Isolated sensitized bronchial rings contracted in response to OA in a concentration-dependent manner, maximum contraction being achieved at 1 microg/ml. Genistein and tyrphostin 47 concentration-dependently (10-100 microM) inhibited OA-induced anaphylactic contraction of the bronchi, as well as release of histamine and peptidoleukotrienes from chopped lung preparations. Genistein, but not tyrphostin 47, significantly suppressed bronchial contraction to leukotriene D4 at 50 microM and to histamine at 100 microM. Daidzein, an inactive congener of genistein, did not alter OA-induced anaphylactic contraction. However, it slightly reduced bronchial contraction to leukotriene D4 and the OA-stimulated release of peptidoleukotrienes. The inhibitory effects were significantly weaker than those of genistein. Taken together, our results show that tyrphostin 47 inhibited anaphylactic contraction mainly by preventing mast cell degranulation, whereas genistein exerted inhibitory effects partly by blocking mast cell degranulation and partly by attenuating leukotriene D4-induced bronchial contraction. These findings suggest that protein tyrosine kinase inhibitors have a therapeutic potential as mast cell stabilizers in the treatment of allergic diseases such as bronchial asthma.
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PMID:Effects of tyrosine kinase inhibitors on antigen challenge of guinea pig lung in vitro. 933 17

Activation of nontransmembrane protein tyrosine kinases (PTKs), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) has been shown to be responsible for high-affinity Fc receptor (Fcepsilon RI)-mediated mast cell degranulation. Effects of inhibitors of the PTK signaling cascade on ovalbumin (OA)-induced anaphylactic contraction of isolated guinea-pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations were studied. Genistein (30 microM) and tyrphostin 47 (50 microM), two PTK inhibitors, as well as LY294002 (10 microM), a selective PI3K inhibitor, significantly reduced (p < 0.05) peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. PD 098059 (30 microM), a selective MAPK kinase inhibitor, failed to suppress OA-induced peak bronchial contraction, but facilitated the relaxation of the contracted bronchi (p < 0.05). At the same concentrations, none of these inhibitors showed any inhibitory effects on histamine-, leukotriene D(4) (LTD(4))- or KCl-induced bronchial contraction. On the other hand, these inhibitors significantly prevented (p < 0.05) OA-induced release of both histamine and peptidoleukotrienes from chopped lung preparations. In addition, combined PD 098059 and LY294002 treatment markedly (p < 0.05) suppressed the peak anaphylactic bronchial contraction and facilitated relaxation of the contracted bronchi. The combination of these two inhibitors further inhibited the release of peptidoleukotrienes from chopped lung preparations. Taken together, our data show that inhibition of tyrosine kinase signaling cascade can markedly attenuate anaphylactic contraction of airways, probably via inhibition of mast cell degranulation, and that inhibitors of this signaling cascade may have therapeutic potential for the treatment of asthma.
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PMID:Inhibitors of tyrosine kinase signaling cascade attenuated antigen challenge of guinea-pig airways in vitro. 1090 31

Although genistein has been demonstrated to induce apoptosis of various cells, there is no report of its effect on mast cell proliferation. Here we show that genistein reduced the viability of mast cell tumor cell lines, p815 and RBL-2H, but not of a human mast cell line, HMC-1. Further investigation on its growth-inhibitory mechanism was undertaken on p815 mastocytoma cells. Genistein induced G2/M arrest and subsequent apoptotic death. p815 cells undergoing apoptosis showed many apoptotic manifestations, such as reduction of mitochondrial membrane potential, release of cytochrome c to cytosol, translocation of apoptosis-inducing factor to nucleus, activation of caspase-3, nuclear condensation, and generation of DNA fragmentation. Genistein treatment resulted in the increase of Bax expression and its translocation into mitochondria, whereas expression levels of Bcl-2 remained unchanged. Proteasome activity decreased at the early time points after genistein treatment, but thereafter it fluctuated at increased levels. A proteasome inhibitor, lactacystin, potentiated the induction of apoptosis. Taken together, genistein-induced apoptosis of p815 mastocytoma cells is at least in part mediated by proteasome, Bax, apoptosis-inducing factor, and caspase and augmented by cotreatment with a proteasome inhibitor, lactacystin.
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PMID:Genistein-induced apoptosis of p815 mastocytoma cells is mediated by Bax and augmented by a proteasome inhibitor, lactacystin. 1241 67

Mast cells are involved in allergic inflammation and some rare disorders such as systemic mastocytosis and mast cell leukemia. Certain naturally occurring flavonoids have been shown to inhibit mast cell activation and promote maturation of secretory granules. Here, we report that the isoflavone genistein inhibited the growth of human leukemic mast cells (HMC-1) by 68.8, 51.6, and 30.2% at 10(-4), 10(-5), and 10(-6) M, respectively, at day 3 (p < 0.001). Genistein at 10(-4) M increased the histamine content per 2 x 10(5) cells at day 3 from 5.9 +/- 1.2 micrograms/mL to 11.1 +/- 1.3 micrograms/mL (n = 6; p < 0.0001). These results indicate that genistein can inhibit proliferation and induce maturation of HMC-1 cells.
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PMID:The isoflavone genistein inhibits proliferation and increases histamine content in human leukemic mast cells. 1461 39

Alkalinization of cytosolic pH with ammonium chloride (NH4Cl) was reported to be a stimulus for mast cell degranulation. This paper studied the modulatory role of drugs that target protein kinase C (PKC), adenosine 3',5'-cyclic monophosphate (cAMP), tyrosine kinase (TyrK) and phosphatidylinositol 3-kinase (PI3K) on this effect. We used Go6976 (100 nM) and low concentrations of GF109203X (Gf) (50 nM) to inhibit calcium-dependent PKC isozymes. For calcium-independent isozymes, we used 500 nM Gf, and 10 microM rottlerin to specifically inhibit PKC delta, and chelerythrine as non-specific PKC inhibitor. Genistein (10 microM) and lavendustin A (1 microM) were used as unspecific TyrK inhibitors, and 10 nM wortmannin as a PI3K inhibitor. Chelerythrine and 50 nM Gf inhibit histamine release in the presence of external calcium. The inhibition caused by wortmannin was strictly internal calcium-dependent. cAMP-active drugs did not modify the response to NH4Cl. The effect of NH4Cl on histamine release was triggered by a transient elevation on cytosolic pH, which was simultaneous to an elevation on cytosolic calcium and followed by a probable Ca2+-H+ exchange after addition of external calcium. EGTA inhibit the response to suboptimal concentrations of NH4Cl, and BAPTA increased the effect of NH4Cl. There is a clear relationship between NH4Cl-mediated calcium release and histamine release, since those drugs that inhibit this release also inhibit NH4Cl-mediated histamine release; nevertheless, NH4Cl-mediated histamine release was possible in the absence of any calcium release, as shown with BAPTA. This data, in combination with the results with PKC inhibitors, suggest that calcium is not only unnecessary to trigger cell activation, but also that it may be a negative modulator of NH4Cl-mediated exocytosis.
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PMID:Calcium-pH crosstalks in rat mast cells: modulation by transduction signals show non-essential role for calcium in alkaline-induced exocytosis. 1562 84


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