UNIPROT:P15088 - FACTA Search

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

The nerve growth factor (NGF) is widely distributed in the target tissues of sympathetic neurons. Hemopoietic organs such as the bone marrow (BM) and spleens are known to be innervated by noradrenergic sympathetic neurons. Some of their constitutive cells express NGF receptors (lymphocytes and stroma cells) and its biologic effects have been extensively studied in the immune system and inflammatory responses. However, the effects of NGF on hemopoiesis have been little examined. Recently, we demonstrated that NGF promoted mast cell colony formation from murine BM cells (BMC) or BMC-derived cultured mast cells and induced the phenotypic changes in standard hemopoietic assays. Besides, we demonstrated NGF-enhanced murine neutrophil survival and functional properties. In this study, in order to investigate NGF activities on neutrophil differentiation, we examined granulocyte-macrophage (GM) colony formation from murine BMC or spleen cells (SC) in the methylcellulose culture. We also assessed mast cell colony formation. GM colonies were counted on day 5 and mast cell colonies were counted on day 20 in culture. Although NGF alone (50 ng/ml) neither supported GM nor mast cell colony formation, addition of various doses of NGF to the suboptimal dose of pokeweed mitogen-stimulated SC-conditioned medium (2.5%) or interleukin 3 (50 U/ml), well-known colony-stimulating factors, increased the number of GM and mast cell colonies from both BMC and SC in a dose-dependent manner. These colony formation-enhancing effects of NGF were inhibited by the addition of neutralizing sheep anti-NGF antibodies. The results suggest that NGF may act to develop granulopoiesis including neutrophil and mast cell differentiation in cooperation with hemopoietic factor(s) during inflammatory processes.
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PMID:Murine granulocyte-macrophage and mast cell colony formation promoted by nerve growth factor. 824 98

To establish the method for generating a large number of mature human mast cells, we cultured cord blood mononuclear cells (CBMC) in several conditions in the presence of Steel factor (SF). Among several cytokines tested, IL-6 enhanced SF-dependent mast cell growth from purified CD34+ cells for more than 8 wk in culture. When CBMC were cultured instead of CD34+ cells, IL-6 enhanced the mast cell development in the presence but not in the absence of PGE2. PGE2 enhanced the SF- and IL-6-dependent development of mast cells from CBMC probably by blocking granulocyte-macrophage CSF (GM-CSF) secretion from accessory cells, because 1) PGE2, or anti-GM-CSF enhanced the mast cell development induced by SF and IL-6 from CBMC, but not from CD34+ cells; 2) GM-CSF inhibited the enhancing effect of IL-6 on the mast cell development from CD34+ cells; and 3) PGE2 inhibited GM-CSF secretion from CBMC. The mast cells cultured in the presence of SF, IL-6, and PGE2 for >10 wk were 99% pure, and seemed to be functionally mature, because 1) they contained 5.62 micrograms of histamine and 3.46 micrograms of tryptase per 10(6) cells; and 2) when sensitized with human IgE and then challenged with anti-human IgE, the cells released a variety of mediators such as histamine, and an increase in intracellular Ca2+ was found in advance of the activation of membrane movement by using a confocal laser-scanning microscope. Electron-microscopic analysis revealed that some of the cultured mast cells are morphologically mature since they filled with scroll granules and contained crystal granules.
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PMID:Selective growth of human mast cells induced by Steel factor, IL-6, and prostaglandin E2 from cord blood mononuclear cells. 868 36

The effects of recombinant human granulocyte CSF (rhG-CSF) and recombinant human granulocyte-macrophage CSF (rhGM-CSF) on the recombinant human stem cell factor (rhSCF)-dependent development of human mast cells from fetal liver progenitors were examined. Mast cells were identified by immunohistochemical staining for tryptase and by flow cytometric analysis of surface Kit expression. Only rhGM-CSF affected mast cell development. When rhGM-CSF (1, 10, or 100 ng/ml) and rhSCF (50 ng/ml) were added to cell cultures from day 0, both the percentage and absolute numbers of mast cells were diminished after 4 wk compared with cultures exposed to rhSCF alone. Half of the maximal response was achieved at a dose of rhGM-CSF between 0.1 and 1 ng/ml. The Kit+ cells developing in the presence of rhGM-CSF and rhSCF exhibited an intensity of surface Kit expression comparable to that of cells exposed to rhSCF alone. Also, if the initial exposure to rhGM-CSF was delayed for 1 to 3 wk, attenuation of mast cell development waned. These findings are consistent with uncommitted progenitor cells being diverted to nonmast cell lineages by rhGM-CSF, while cells committed to a mast cell lineage, albeit immature, appear to be resistant to the lineage directives of rhGM-CSF. Exposure of fetal liver cells to rhGM-CSF for 1 to 3 days before addition of rhSCF further diminishes the number of mast cells that develop compared with the simultaneous addition of these growth factors on day 0. Whether administration of rhGM-CSF to humans before or together with rhSCF diminishes the mast cell hyperplasia that occurs with rhSCF alone remains to be determined.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor (CSF), but not recombinant human granulocyte CSF, down-regulates the recombinant human stem cell factor-dependent differentiation of human fetal liver-derived mast cells. 921 2

To examine the relation between receptor expression and differentiation of hematopoietic cells, we produced transgenic mice that constitutively expressed the human granulocyte-macrophage colony stimulating factor (hGM-CSF) receptor at almost all stages of hematopoietic cell development. The high-affinity GM-CSF receptor is species specific, allowing analysis of the specific effects of hGM-CSF in our mouse model. Proliferation and differentiation of hematopoietic progenitor cells from transgenic mice were analyzed by means of methylcellulose colony-forming assay and in vivo treatment with hGM-CSF, respectively. We found that hGM-CSF supported various types of colonies, including granulocyte-macrophage, mast cell, megakaryocyte, blast cell, and mixed hematopoietic colonies, whereas mouse GM-CSF supported only granulocyte-macrophage colonies. In addition, hGM-CSF generated erythrocyte colonies in the absence of erythropoietin. Furthermore, in vivo administration of hGM-CSF to transgenic mice resulted in a dose-dependent increase in reticulocytes and white blood cells in the peripheral blood. The spleens of the mice showed gross enlargement, mainly caused by an increase of erythroid cells and their progenitors. Taken together, these results indicate that hGM-CSF receptor-mediated signals can support the growth of cells of all hematopoietic cell lineages if this receptor is present on the cell surface. This implies that the differentiation of hematopoietic progenitor cells is not determined by exogenous cytokine stimulation (instruction model) but by an intrinsic cell program in which cytokines simply select cells that express the appropriate receptor (stochastic model).
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PMID:Human granulocyte-macrophage colony-stimulating factor (hGM-CSF)-dependent in vitro and in vivo proliferation and differentiation of all hematopoietic progenitor cells in hGM-CSF receptor transgenic mice. 944 May 51

Mast cell-eosinophil interactions in allergy have not yet been completely defined. To determine whether mast cells influence eosinophil survival, human peripheral blood eosinophils were incubated with rat peritoneal mast cell sonicate. After 3 days, viable eosinophils in medium were 21.3% compared with 44% with mast cell sonicate. Like sonicate, supernatants of compound 48/80-activated mast cells enhanced eosinophil survival, demonstrating that the factor(s) involved is stored preformed and rapidly released. Increased eosinophil survival was due to an inhibition of apoptosis (morphologic analysis; annexin V/PI). Neutralizing Abs to granulocyte-macrophage CSF (GM-CSF), but not to IL-3 or IL-5, decreased by 61.7% the enhancing effect on eosinophil viability. Eosinophils are the source of GM-CSF since its release in the culture medium was inhibited by their incubation with the mast cell sonicate together with dexamethasone. In addition, eosinophils incubated with the sonicate expressed mRNA for GM-CSF. To partially characterize the mast cell-derived factor(s) increasing eosinophil survival, the sonicate was heated (56 degrees C/30 min or 100 degrees C/10 min) or preincubated with antihistamines or with anti-TNF-alpha-neutralizing Abs. Most of the activity was heat labile. TNF-alpha was found to be predominantly (70%) responsible, while histamine had no role. Mast cell sonicate also caused eosinophils to release eosinophil peroxidase and to display morphologic signs of activation. In conclusion, we have demonstrated that mast cells enhance eosinophil survival in part through their activation to produce and release the autocrine survival cytokine GM-CSF.
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PMID:Mast cells enhance eosinophil survival in vitro: role of TNF-alpha and granulocyte-macrophage colony-stimulating factor. 960 60

Mast cells are found frequently in close proximity to blood vessels, and endothelial cells are likely to be exposed to high concentrations of their granule mediators. We have investigated the proinflammatory actions of the major mast cell product tryptase on HUVEC. Addition of purified tryptase was found to stimulate thymidine incorporation, but induced little alteration in cell numbers, suggesting it is not a growth factor for HUVEC. Expression of ICAM-1, VCAM-1, and E-selectin was not altered following incubation with tryptase, but the potent granulocyte chemoattractant IL-8 was released in a dose-dependent fashion in response to physiologically relevant concentrations, with maximal levels in supernatants after 24 h. The actions of tryptase on HUVEC were inhibited by heat inactivation of the enzyme, or by preincubating with the protease inhibitors leupeptin or benzamidine, suggesting a requirement for an intact catalytic site. Reverse-transcription PCR analysis indicated up-regulation of mRNA for IL-8 as well as for IL-1 beta in response to tryptase or TNF-alpha. However, tryptase was a more selective stimulus than TNF-alpha and did not induce increased expression of mRNA for granulocyte-macrophage CSF or stimulate the release of this cytokine. Leukocyte accumulation in response to tryptase may be mediated in part through the selective secretion of IL-8 from endothelial cells.
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PMID:The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells. 971 64

Ets-1 is a transcription factor with restricted expression in lymphocytes, and it has been implicated in the regulation of T cell genes such as TCR alpha, TCR beta, CD4, IL-2, and TNF-alpha. We show in this study that Ets-1 is also expressed in some mast cells constitutively and can be induced in primary mast cells with stimuli that activate mast cells. We also show that Ets-1 plays a role in the regulation of granulocyte-macrophage CSF (GM-CSF), a cytokine expressed by activated mast cells. We have characterized a murine growth factor-independent mast cell line, FMP6-, derived from a factor-dependent cell line, FMP1.6. FMP6- has acquired a distinct connective tissue mast cell-like phenotype, as characterized by the expression of mast cell proteases MMCP-4 and MMCP-6, expression of IL-12, and the down-regulation of IL-4. The parental FMP1.6 cell line displays a mucosal mast cell-like phenotype. FMP6- cells have increased Ets-1 expression and achieve growth-factor independence by the autocrine production of GM-CSF and IL-3. Transient transfection of an Ets-1 expression construct in FMP6- cells results in transactivation of a GM-CSF reporter, while a point mutation in the consensus Ets binding site in the conserved lymphokine element, CLE0, abolishes Ets-1 transactivation. Importantly, antisense Ets-1 demonstrates an ability to repress the activity of the GM-CSF reporter. These data suggest a role for Ets-1 in mast cell growth regulation and activation, and because of the central role of mast cells in inflammatory processes, such as asthma and rheumatoid arthritis, they identify Ets-1 as potentially contributing to the pathophysiology of such diseases.
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PMID:The role of Ets-1 in mast cell granulocyte-macrophage colony-stimulating factor expression and activation. 978 Jan 81

Human mast cells are derived from CD34(+) hematopoietic cells present in cord blood, bone marrow, and peripheral blood. However, little is known about the properties of the CD34(+) cells. We demonstrated here that mast cell progenitors that have distinct phenotypes from other hematopoietic cell types are present in cord blood by culturing single, sorted CD34(+) cells in 96-well plates or unsorted cells in methylcellulose. The CD34(+) mast cell-committed progenitors often expressed CD38 and often lacked HLA-DR, whereas CD34(+) erythroid progenitors often expressed both CD38 and HLA-DR and CD34(+) granulocyte-macrophage progenitors often had CD33 and sometimes expressed CD38. We then cultured single cord blood-derived CD34(+)CD38(+) cells under conditions optimal for mast cells and three types of myeloid cells, ie, basophils, eosinophils, and macrophages. Of 1,200 CD34(+)CD38(+) cells, we were able to detect 13 pure mast cell colonies and 52 pure colonies consisting of either one of these three myeloid cell types. We found 17 colonies consisting of two of the three myeloid cell types, whereas only one colony consisted of mast cells and another cell type. These results indicate that human mast cells develop from progenitors that have unique phenotypes and that committed mast cell progenitors develop from multipotent hematopoietic cells through a pathway distinct from myeloid lineages including basophils, which have many similarities to mast cells.
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PMID:Characterization of mast cell-committed progenitors present in human umbilical cord blood. 1023 86

The stem cell leukemia (SCL) gene encodes a basic helix-loop-helix transcription factor expressed in erythroid, megakaryocyte, and mast-cell lineages. SCL is essential for growth of megakaryocyte and erythroid progenitors. We have used a conditional knockout of SCL (SCL(-/Delta)) to examine its function in mast cells, critical effectors of the immune system. SCL(-/Delta) mice had markedly increased numbers of mast-cell progenitors (MCPs) within the peritoneal fluid, bone marrow, and spleen. Fractionation of bone marrow myeloid progenitors demonstrated that these MCPs were present in the megakaryocyte-erythroid-restricted cell fraction. In contrast, unilineage MCPs from control mice were present in the cell fraction with granulocyte-macrophage potential. The aberrant mast-cell differentiation of SCL(-/Delta) megakaryocyte-erythroid progenitors was associated with increased expression of GATA-2. Despite increased numbers of MCPs in SCL(-/Delta) mice, numbers of mature tissue mast cells were not increased unless SCL(-/Delta) mice were treated with IL-3 and stem-cell factor. In part, this may be due to a requirement for SCL in normal mast-cell maturation: SCL(-/Delta) mast cells had reduced expression of the high-affinity IgE receptor and mast cell proteases, MCP-5 and MCP-6. Together, these studies suggest that loss of SCL leads to aberrant mast-cell differentiation of megakaryocyte-erythroid progenitors.
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PMID:Aberrant mast-cell differentiation in mice lacking the stem-cell leukemia gene. 1764 41

Mast cells are thought to participate in a wide variety of pathophysiological conditions. Mechanisms of regulation, however, of mast cell production and maturation are still to be elucidated. Mast cell developmental process is likely to be profoundly affected by cell-autonomous transcriptional regulators such as the GATA family and CCAAT/enhancer binding protein (C/EBP) family members. Extracellular regulators such as stem cell factor and IL-3 have essential roles in basal and inducible mast cell generation, respectively. The relationship, however, between the extracellular signaling and cellular transcriptional control is unclear, and the trigger of the mast cell development remains elusive. Notch signaling plays a fundamental role in the lymphopoietic compartment, but its role in myeloid differentiation is less clear. Here, we demonstrate that Notch signaling connects environmental cues and transcriptional control for mast cell fate decision. Delta1, an established Notch ligand, instructs bone marrow common myeloid progenitors and granulocyte-macrophage progenitors toward mast cell lineage at the expense of other granulocyte-macrophage lineages, depending on the function of the Notch2 gene. Notch2 signaling results in the up-regulation of Hes-1 and GATA3, whereas simultaneous overexpression of these transcription factors remarkably biases the progenitor fate toward the mast cell-containing colony-forming cells. C/EBPalpha mRNA was down-regulated in myeloid progenitors as a consequence of Hes-1 overexpression, in agreement with the recent proposal that the down-regulation of C/EBPalpha is necessary for mast cell fate determination. Taken together, signaling through Notch2 determines the fate of myeloid progenitors toward mast cell-producing progenitors, via coordinately up-regulating Hes-1 and GATA3.
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PMID:Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate. 1851 23

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