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)

Receptor tyrosine kinases are known to be important in growth and differentiation. We have recently found that c-kit, the tyrosine kinase receptor for steel factor, also regulates cell-matrix adhesion. Because Steel factor helps regulate cell migration and localization, this may be an important biologic function. Integrin adhesiveness is regulated within minutes by c-kit. The signaling pathways for tyrosine kinase stimulation of integrin adhesiveness and their relation to pathways that regulate growth and differentiation over much longer time periods remain uncharacterized. We have studied the effector pathways by which receptor tyrosine kinases regulate cell-matrix adhesion using wild-type and mutant forms of the platelet-derived growth factor (PDGF) receptor, which is closely related to c-kit. The PDGF receptor expressed in mast cells is as potent as c-kit in stimulating adhesion to fibronectin. We show that induction of adhesion is regulated through two independent pathways of phosphatidylinositol 3 kinase (PI3K) and phospholipase C-gamma 1 (PLC gamma)-protein kinase C by elimination of autophosphorylation sites required for activation of PI3K and PLC gamma or in combination with downregulation of protein kinase C or wortmannin. By contrast, a receptor mutated in both the PI3K and PLC gamma association sites can still stimulate mast cell growth, indicating a crucial role of these effector molecules in regulating adhesion rather than cell growth.
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PMID:Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase C-gamma 1 pathways. 754 20

Mast cells accumulate at sites of angiogenesis. The factor(s) that control mast-cell recruitment at these sites have yet to be defined. We sought to determine if angiogenic factors result in mast-cell chemotaxis. In this study, we observed that platelet-derived growth factor-AB (PDGF-AB), vascular endothelial cell growth factor (VEGF), and basic fibroblast growth factor (bFGF) each cause directed migration of murine mast cells at picomolar concentrations, with a typical bell-shaped dose-response curve. Another potent angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), appears to promote chemokinesis of mast cells, whereas tumor necrosis factor-alpha, a weak angiogenic factor, is less robust but still functions as a mast cell chemotactic factor. Epidermal growth factor (EGF), a growth factor with minimal angiogenic properties, was ineffective as a mast cell chemotactic factor. A checkerboard analysis confirmed the directional chemotactic response of PDGF-AB, VEGF, and bFGF, while indicating the chemokinetic response induced by PD-ECGF. Cross-desensitization of growth-factor-induced directed migration was observed between PDGF-AB and bFGF, and also between PDGF-AB and PD-ECGF. Tyrosine kinase-inhibitor genistein effectively dampened the chemotactic responses, whereas pertussis toxin had no effect. In summary, our findings suggest that factors known to act on endothelial cells and stimulate neovascularization may simultaneously serve to recruit mast cells to these sites. The local accumulation of mast cells is believed to facilitate new vessel formation through complex cell:cell interactions.
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PMID:Angiogenic factors stimulate mast-cell migration. 754 57

Hyperplasia of airway smooth muscle cells is present in the airways of asthmatic patients and may contribute to the development of the bronchial hyperresponsiveness that occurs in these patients. Because tryptase is an abundant component of mast cell granules and has demonstrated growth-stimulatory effects in other mesenchymal cells (J. Clin. Invest. 1991; 88:493-499), the goal of our study was to determine whether tryptase is a mitogen for airway smooth muscle cells. The mitogenic effects of tryptase were tested in passages 1 through 5 of dog tracheal smooth muscle cells, either by counting smooth muscle cells or by monitoring uptake of bromodeoxyuridine (BrdU) into cellular DNA during S-phase. With respect to its efficacy, at a near maximal concentration (4 nM), tryptase increased cell numbers 2.1 +/- 0.2- or 2.8 +/- 0.6-fold above controls after 2 or 4 days, respectively, and these increases were approximately the same as those induced by platelet-derived growth factor (50 ng/ml) or 10% calf serum. With respect to potency, tryptase caused concentration-dependent increases in BrdU uptake, as detected in an enzyme-linked immunosorbent assay or by counting BrdU-labeled nuclei, with an EC50 of 2 nM. Pretreatment of tryptase with diisopropylfluorophosphate, to reduce markedly its catalytic as a activity as a proteinase, attenuated its growth-stimulated effects by 58 +/- 16%. Tryptase-induced mitogenesis was not a nonspecific effect of all serine proteinases, because thrombin, another proteinase with mitogenicity for fibroblasts, stimulated neither increases in cell counts nor BrdU uptake in our cells. We conclude that tryptase is a potent mitogen for airway smooth muscle cells in culture.
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PMID:Tryptase, the dominant secretory granular protein in human mast cells, is a potent mitogen for cultured dog tracheal smooth muscle cells. 762 90

The human basophilic cell line KU 812, that also has some mast cell characteristics, was found to express the PDGF-A gene and secrete PDGF-A like activity. After treatment with IL-6+ TNF-alpha, the PDGF-A mRNA expression increased as did cytoplasmic immunostaining with anti-PDGF antibodies. Secretion of PDGF-A was visualized by immunoprecipitation. An augmentation of non-secreted PDGF-like activity after IL-6+ TNF-alpha treatment was not accompanied by induction of the long splice variant of the PDGF-A-chain mRNA. Treatment with TPA caused an increase in PDGF-A expression and in addition, an induction of PDGF-B transcripts were seen. Staining of cytospin preparations with anti-PDGF antibodies visualized a substantial increase in immunostaining of the TPA treated cells and both intracellular and secreted PDGF-AA-like activity was substantially increased as compared to untreated control cultures. There was a concomitant induction of exon 6 specific mRNA, corresponding to a cellular retention signal after TPA treatment. Our results show that PDGF can be produced by a cell line of the basophilic/mast cell lineage, i.e. cells involved in allergic disorders and inflammation.
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PMID:Constitutive and inducible expression of PDGF in the human basophilic cell line, KU 812. 827

The beta-type receptor of platelet-derived growth factor (beta PDGFR) is a class III transmembrane receptor with tyrosine kinase activity. The beta PDGFR gene is located on mouse chromosome 18 close to the c-fms gene which codes for the colony stimulating factor-1 receptor (CSF-1R). We previously reported that in a high percentage of myeloblastic leukemias induced by the Friend helper murine leukemia virus (F-MuLV), proviruses were integrated in the first intron of the c-fms gene leading to an enhanced expression of c-fms mRNA. Since activation by proviral insertion can act at long distance, we studied beta PDGF receptor gene expression in murine myeloblastic leukemias. This gene was found to be frequently expressed but the level of beta PDGF receptor mRNA was weak and not related to proviral activation. High affinity binding sites were expressed on myeloblastic cells and ligand binding induced cell proliferation. To determine whether beta PDGFR expression is a common feature in hematopoietic cells, we tested cell lines belonging to other hematopoietic lineages. We found that multipotent stem and mast cell lines also expressed the beta PDGF receptor gene. This suggests that PDGF, known as a mitogen for connective tissue cells, could also play a role in normal hematopoiesis.
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PMID:Expression of functional beta-platelet-derived growth factor receptors on hematopoietic cell lines. 848 8

Mast cells have been implicated in the pathogenesis of fibrosis because of their increased number in chronic inflammatory reactions. In a previous study, we had shown that human mast cells readily attach and form heterotypic cell-cell contacts when seeded on top of fibroblast monolayers. Here, we report that human mast cells stimulate fibroblast proliferation after cell-cell contact. Proliferation was measured by 5-bromo-2'-deoxyuridine or [3H]thymidine uptake of subconfluent fibroblast monolayers after attachment of mast cells that had been preincubated with mitomycin C. An 18-h coculture of the human mast cell line HMC-1 doubled proliferation of normal skin fibroblasts. Moreover, normal mast cells prepared from neonatal foreskin doubled fibroblast proliferation. The stimulatory effect was dependent on heterotypic cell-cell contact since it was not transferred by tissue culture supernatants from mast cells. We hypothesized that mast cell cytokines secreted after heterotypic cell-cell contact stimulate fibroblast proliferation. Several mast cell-derived cytokines were tested for effects on fibroblast proliferation. Only IL-4 was able to double fibroblast proliferation. Additional experiments revealed that: 1) the stimulatory effect of IL-4 as well as of the mast cell coculture could be completely abrogated by preincubation of fibroblasts with an anti-IL-4R mAb blocking ligand binding; 2) mast cell-derived IL-4 acts as a second signal for fibroblasts since it amplifies the action of low doses of obligatory fibroblast growth factors such as fibroblast growth factor or platelet-derived growth factor.
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PMID:Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. 959 Feb 55

Mast cell hyperplasia is often observed in dermatoses characterized by fibrosis. Evidence has accumulated showing that a potent fibrogenic cytokine, platelet-derived growth factor (PDGF), plays a pathogenic role in dermal fibrosis. To clarify the mechanism of mast cell hyperplasia associated with fibrosis, we investigated the effect of PDGF on mast cell proliferation and the expression of stem cell factor (SCF), a potent growth factor for mast cells, in fibroblasts. When mouse bone marrow-derived mast cells (BMMC) were cultured on a NIH/3T3 fibroblast monolayer, mast cell proliferation was stimulated in both cell number and total histamine content by all isoforms of PDGF (-AA, -AB, and -BB); however, none of the isoforms had any effect on [3H] thymidine incorporation in BMMC in the absence of fibroblasts. The effect of PDGF-AB and -BB were abrogated either by the addition of anti-PDGF-AB antibody or by the separation of mast cells and fibroblasts by a permeable membrane filter with a pore size of 0.2 microm. Immunoblotting of the NIH/3T3 fibroblasts treated with PDGF revealed an enhanced expression of SCF in the membrane fraction and the effect of PDGF was neutralized by the addition of antibody against SCF. Moreover, no effect of PDGF was observed when BMMC were prepared from W/W(v) mice that lack functional c-kit as the SCF receptor or when 3T3 fibroblasts were prepared from Sl/Sl(d) mice that lack membrane-bound SCF. These results suggest that the fibrogenic cytokine PDGF stimulates mast cell hyperplasia via the expression of membrane-bound SCF by fibroblasts in association with fibrosis of the skin.
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PMID:A fibrogenic cytokine, platelet-derived growth factor (PDGF), enhances mast cell growth indirectly via a SCF- and fibroblast-dependent pathway. 969 19

The increase in the amount of airway smooth muscle in the bronchial wall associated with asthma is partly due to hyperplasia. It is therefore important to determine which factors regulate growth and especially proliferation. In this study, we describe the effect of interleukin-4 (IL-4), a mast cell- and T lymphocyte-derived cytokine, on human airway smooth muscle proliferation as determined by [3H]thymidine uptake in the presence of fetal bovine serum (FBS), platelet-derived growth factor, basic fibroblast growth factor, and thrombin. IL-4 (5, 15, 50, and 150 ng/ml) significantly decreased 10% FBS-induced proliferation by 50, 73, 43, and 46%, respectively. The proliferative responses to platelet-derived growth factor (20 and 40 ng/ml), basic fibroblast growth factor (30 ng/ml), and thrombin (1 and 10 U/ml) were significantly reduced by 19, 21, 37, 36, and 57% respectively in the presence of 50 ng/ml of IL-4. We investigated the effect of IL-4 and other known inhibitors of smooth muscle proliferation, namely PGE2, heparin, and forskolin, on intracellular cAMP concentrations. IL-4 (50 ng/ml) and heparin (100 U/ml) did not alter intracellular cAMP levels when cells were treated with 1 or 10% FBS. PGE2 (1 microM) and forskolin (10 microM) significantly increased cAMP concentration above the control value in nonproliferating cells (1% FBS treated) by 7- and 37-fold, respectively. The effect of IL-4 (50 ng/ml), PGE2 (1 microM), and forskolin (10 microM) on cyclin D1 protein expression in 10% FBS-stimulated human airway smooth muscle cells was also examined. PGE2 and forskolin did not significantly inhibit cyclin D1 expression. However, IL-4 decreased cyclin D1 expression by 21%. These results provide evidence that IL-4 decreases human airway smooth muscle cell proliferation via a mechanism that is cAMP independent and mediated, in part, by a decrease in cyclin D1 protein expression.
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PMID:Interleukin-4 inhibits mitogen-induced proliferation of human airway smooth muscle cells in culture. 972 41

We have previously shown that fibroblast and keratinocyte supernatants up-regulate expression of mast cell characteristics in the human immature mast cell line HMC-1. This effect could not be induced in HMC-1 cells by the well-known mast cell growth factor stem cell factor (SCF), probably due to mutations of the SCF receptor c-Kit in these cells. Here we report the effects of several known fibroblast- and keratinocyte-derived growth factors, namely nerve growth factor (NGF), basic fibroblast growth factor, platelet-derived growth factor and transforming growth factor-beta, on mast cell differentiation, using HMC-1 cells as a model. NGF, at 0.1-50 ng/ml concentrations, caused a marked, dose-dependent up-regulation of tryptase, Fc epsilon RI and histamine within 10 days of culture, associated with an enhanced expression of mRNA for Fc epsilon RI and mast cell tryptase. On restriction analysis, only mast cell beta-tryptase, but not alpha-tryptase, could be demonstrated. Furthermore, the high-affinity NGF receptor (TrkA) was found at both the transcriptional and protein levels, while expression of the low-affinity NGF receptor was detectable at the mRNA level only. None of the other growth factors caused a significant alteration of the mast cell markers studied when added to HMC-1 cells at concentrations known to be biologically active in other culture systems. Immature human mast cells are thus induced to assume a more mature phenotype in vitro in response to NGF, most probably via stimulation of the high-affinity NGF receptor expressed on these cells. Besides SCF, NGF should therefore be considered as an additional mast cell growth factor that contributes to human mast cell maturation at tissue sites.
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PMID:Effects of nerve growth factor (NGF) and other fibroblast-derived growth factors on immature human mast cells (HMC-1). 977 35

Mastocytosis is a rare stem cell disorder characterized by abnormal growth and accumulation of mast cells in one or more organ systems. Clinical heterogeneity is a hallmark of mastocytosis. Recent observations of activating mutations in c-kit may help to understand the abnormal growth of mast cells in mastocytosis. However, this mutation alone does not explain the entire clinical heterogeneity of the disease. Reticulin fibrosis is also commonly associated with systemic mastocytosis. Mast cells are known to be the source of fibrogenic cytokines, including platelet-derived growth factor, transforming growth factor-beta (TGF beta) and basic fibroblast growth factor (bFGF). Immunohistochemical studies show a close correlation between the mast cell expression of bFGF and the reticulin fibrosis of mastocytosis lesions. The study of cytokine receptor expression also demonstrates that the TGF beta receptor I (RI)-negative cases of mastocytosis are prognostically less favorable than the TGF beta RI-positive cases. This finding may be related to the fact that the TGF beta R complex functions as a tumor suppressor gene in neoplastic cells.
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PMID:Mastocytosis and fibrosis: role of cytokines. 1191 21


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