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)

Mast cells and blood basophils are distinct hemopoietic cells. They can be distinguished from each other and from all other lymphohemopoietic cells using antibodies against surface receptors or stored cytoplasmic molecules. In patients with myelodysplastic syndromes (MDS) or myeloproliferative syndromes (MPS), an elevation of metachromatically granulated cells (MCS) is frequently seen. These cells can be classified as basophils or mast cells using monoclonal antibodies (mAbs) against leukocyte antigens, including mast cell tryptase, c-kit (= mast cell growth factor [MGF] receptor), interleukin-3 receptor alpha chain (IL-3R alpha = CD123), and CD11b (C3biR). In a stable phase of MDS or MPS, the circulating MCS usually are basophils (histamine+, tryptase-, c-kit-, IL-3R alpha +, CD11b+). In an accelerated or terminal phase of disease, however, mast cell lineage involvement and circulating mast cell precursors (histamine+, tryptase+, c-kit+, IL-3R alpha-, CD11b-) are found in a subset of patients. The use of mAbs against mast cell antigens and granulocyte antigens is diagnostic in these patients.
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PMID:Mast cell-lineage versus basophil lineage involvement in myeloproliferative and myelodysplastic syndromes: diagnostic role of cell-immunophenotyping. 881 68

In previous studies we have noted that mast cells are increased in tretinoin-treated photoaged hairless mouse skin. Because UV radiation is known to increase mast cell numbers, we were interested in whether tretinoin alone would modulate the mast cell population in unirradiated mice. Animals were treated topically with 0.05% tretinoin, 5 days a week, for 2, 4, 6, 8 and 10 weeks. Untreated and vehicle controls were included. Biopsies were processed for light microscopy and stained with toluidine blue. Mast cells in the upper and lower dermis were scored separately under high magnification. After 2 weeks of tretinoin, mast cells in the upper dermis were significantly increased, as indicated by the appearance of small, moderately metachromatically granulated cells near the dermal-epidermal junction. Mast cells in the lower dermis, the site of a granulomatous reaction, were large, densely granular and significantly increased after 6 weeks of treatment. Immunohistochemical evaluation for mast cell growth factor (MGF) revealed a marked increase in keratinocyte cytoplasmic staining by week 2. After 4-6 weeks, membrane-associated or intercellular staining was evident. Cells in the upper dermis also showed membrane reactivity for MGF. By 8-10 weeks, epidermal MGF reactivity had dissipated in the more basal keratinocytes. These findings show that topical tretinoin can induce epidermal MGF along with an associated mast cell hyperplasia. It is suggested that the two populations of dermal mast cells may have different functions.
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PMID:Topical tretinoin increases dermal mast cells, induces epidermal mast cell growth factor (c-kit ligand) and modulates its distribution in hairless mice. 887 49

Interleukin-15/T(IL-15) is a growth factor that utilizes IL-2 receptor (IL-2R) components in addition to its private binding protein IL-15R(alpha) in T-cells. Here, we report that IL-15 induces mast cell proliferation in the absence of IL-2R alpha and beta. Using transfectants of these cells with a cytoplasmic-truncated mutant of gamma(c), we demonstrated that IL-15 signaling in mast cells does not involve gamma(c). Cross-linking of mast cells with [(125)I]IL-15 revealed a 60-65 kDa IL-15 binding protein that is distinct from known components of T-cell IL-15 receptors. Mast cell IL-15 receptors recruit JAK-2 and STAT-5, instead of JAK1/3 and STAT3/5 that are activated in T-cells. Thus IL-15 is a mast cell growth factor that utilizes a novel receptor and distinct signaling pathway.
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PMID:Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. 889 Jan 66

IgE-mediated Type-I allergic reactions at nematode-infected mucosal surfaces are considered to have a direct protective function. The contribution of mucosal mast cells (MMC) to these mucosal allergic responses is reviewed. In addition to the T helper 2 cell-mediated regulation of MMC hyperplasia during nematode infection the kit ligand, stem cell factor (SCF), plays a key role in the early development of the MMC response. Studies in the mouse suggest that MMC protect against certain nematodes which enter the mucosa but not against lumen dwelling nematodes. The protective roles of MMC in other species, including sheep, are less certain and there is some evidence that MMC might enhance parasite fecundity. The measurement of MMC-specific granule chymases released systemically, and into the gut lumen, permits precise monitoring of mast cell activation and suggests that the secreted chymases may target epithelial junctional complex proteins, thereby causing increased mucosal permeability. The abundant intraepithelial MMC found in parasitised mucosa may, therefore, serve as epithelial gatekeepers permitting the translocation of plasma proteins onto the mucosal surface.
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PMID:Mucosal mast cells and the allergic response against nematode parasites. 898 78

Human mast cell precursors arise in the bone marrow and circulate to different tissue microenvironments, where they develop distinct phenotypes that may be characterized by differential expression of the serine protease, chymase. The growth and development of mast cells is stimulated by mast cell growth factor, which is also known as kit ligand because its obligate receptor is KIT, the protein product of the c-KIT proto-oncogene. The in vivo influence of the KIT-kit ligand axis on the phenotype of human mast cells has not been determined. We used immunohistochemistry to detect in situ expression of tryptase and chymase by mast cells of a patient with urticaria pigmentosa and aggressive systemic mastocytosis, whose pathologic mast cells are clonally derived and chronically stimulated by KIT because they all contain the same point mutation causing constitutive activation of KIT. Mast cells in both spleen and skin expressed tryptase, but only in the skin did a majority of mast cells express chymase. We conclude that chronic stimulation of the KIT-kit ligand axis does not irrevocably commit mast cells to a chymase-positive or chymase-negative phenotype. These findings suggest that factors other than kit ligand predominate in determining mast cell phenotype.
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PMID:Chronically KIT-stimulated clonally-derived human mast cells show heterogeneity in different tissue microenvironments. 945 20

Human skin xenografted to mice with severe combined immunodeficiency syndrome (SCID) was evaluated to determine the integrity and fate of human dermal mast cells. There was an approximately 3-fold increase in number of dermal mast cells by 3 mo after engraftment (p < 0.05). These cells were responsive to conventional mast cell secretagogues and were confirmed to be of human origin by ultrastructural characterization of granule substructure and by reactivity for the human mast cell proteinase, chymase. CD1a+ Langerhans cells, also bone marrow-derived cells, failed to show evidence of concomitant hyperplasia, and increased mast cell number was not associated with alterations in number of dermal vascular profiles identified immunohistochemically for human CD31. RT-PCR analysis demonstrated human but not murine stem cell factor (SCF; also termed mast cell growth factor, c-kit ligand) mRNA in xenografts. Epidermal reactivity for stem cell factor protein shifted from a cytoplasmic pattern to an intercellular pattern by 3 mo after engraftment, suggesting a secretory phenotype, as previously documented for human cutaneous mastocytosis. The majority (>90%) of mast cells demonstrated membrane reactivity for human SCF at the time points of peak hyperplasia. These data establish SCID mouse recipients of human skin xenografts as a potential in vivo model for cutaneous mast cell hyperplasia.
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PMID:Human skin/SCID mouse chimeras as an in vivo model for human cutaneous mast cell hyperplasia. 920 63

The expression of c-kit and flk-2/flt3 was analyzed in various stages of mast cell differentiation using reverse transcriptase polymerase chain reaction (RT-PCR). Mouse fetal liver cells were sorted using antibodies for Sca-1 (Ly6A/E) and CD43 to obtain a population enriched for early progenitors; committed mast cell progenitors were absent from this population. Mouse fetal liver-derived, IL-3-dependent blast cell colonies provided a source of committed mast cell progenitors, and mast cell colonies provided mature mast cells. Comparison of these populations showed that some uncommitted cells express both c-kit and flk-2/flt3. At the time of commitment to the mast cell lineage, the expression of c-kit increases compared to that of uncommitted progenitors, and the expression of flk-2/flt3 becomes undetectable. Previous studies have shown that steel factor, the ligand for c-kit, supports mast cell differentiation in vivo and in vitro. In contrast, the ligand for flk-2/flt3 is inactive on mast cells. Thus, receptor gene expression appears to be an important determinant of the response or lack of response of mast cells to the ligands for these two homologous receptors.
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PMID:Loss of flk-2/flt3 expression during commitment of multipotent mouse hematopoietic progenitor cells to the mast cell lineage. 921 38

The ligand for c-kit, known as stem cell factor, mast cell growth factor, or kit ligand, plays a central role in normal hematopoietic stem cell, melanocyte, and gametocyte development and function during embryogenesis and in adult life. In vitro, stem cell factor promotes the survival of hematopoietic progenitors and enhances their proliferation in response to specific growth factors. Administration of recombinant soluble stem cell factor to rodents, dogs, and baboons produces a broad array of effects on hematopoiesis, though not all lineages are equally stimulated. At doses of more than 100 micrograms/kg/d stem cell factor stimulates neutrophilia, lymphocytosis, basophilia, and reticulocytosis and increases mast cells in multiple tissues. In vivo mast cell activation can occur. Marrow cellularity is increased and progenitor cells are increased in marrow, spleen, and blood, and marrow-repopulating cells are increased in the circulation of stem cell factor-treated animals. Stem cell factor synergizes with other hematopoietic growth factors in vivo. Low-dose stem cell factor, 25 micrograms/kg/d, that does not elicit a detectable biological response, enhances the effects of granulocyte colony-stimulating factor in vivo, increasing the neutrophilia and circulation of progenitor and marrow-repopulating cells above that which is achieved with either factor alone. In phase I human trials, dose-limiting toxicities, related to mast cell activation, were reached at 25 to 50 micrograms/kg/d of recombinant human stem cell factor. At these doses, progenitor and long-term culture-initiating cells are increased in marrow and increases in circulating levels of progenitor cells of multiple types are observed. Phase I-II trials of low-dose stem cell factor in combination with granulocyte colony-stimulating factor show that the combination increases the circulation of CD34+ cells and colony-forming progenitor cells. Further studies are needed to determine the therapeutic role of stem cell factor and its effects on expansion and maintenance of hematopoietic stem cells in vivo.
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PMID:Stimulation of hematopoiesis in vivo by stem cell factor. 937 Dec 81

Myelodysplastic syndromes (MDS) may be accompanied by systemic mastocytosis. The mechanisms which play a role in the evolution of mastocytosis, however, are not well understood. We report on a case of refractory and anemia with ringed sideroblasts (RARS), and co-existing bone marrow mastocytosis. Compact mast cell (MC) infiltrates were detected in bone marrow sections by immunohistochemistry using an antibody to tryptase. In addition, the MC were found to express c-kit, the tyrosine kinase receptor for MGF (mast cell growth factor = stem cell factor, SCF). Activating point mutations in the kinase domain of c-kit (often found in mastocytosis) were not detectable. However, the mononuclear cells (MNC) of the bone marrow expressed mRNA specific for MITF, a transcription factor that regulates expression of c-kit and differentiation of MC. Surprisingly, the c-kit ligand SCF was found to augment expression of MITF mRNA in bone marrow MNC. Whether this augmentation represents a general response (preventing loss of growth factor receptor expression during cell maturation) common to all types of hemopoietic progenitors, or is confined to (some forms of) mastocytosis, remains unknown.
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PMID:Detection of mi transcription factor (MITF) mRNA in a case of myelodysplastic syndrome and bone marrow mastocytosis. 955 2

The Kit ligand (KL)/Kit receptor pair functions in hematopoiesis, gametogenesis, and melanogenesis. KL is encoded at the murine steel (Sl) locus and encodes a membrane growth factor which may be proteolytically processed to produce soluble KL. The membrane-associated form of KL is critical in mediating Kit function in vivo. Evidence for a role of cytoplasmic domain sequences of KL comes from the Sl17H mutation, a splice site mutation that replaces the cytoplasmic domain with extraneous amino acids. Using deletion mutants and the Sl17H allele, we have investigated the role of the cytoplasmic domain sequences of KL in biosynthetic processing and cell surface presentation. The normal KL protein products are processed for cell surface expression, where they form dimers. Both Sl17H and the cytoplasmic deletion mutants of KL were processed to the cell surface; however, the rate of transport and protein stability were affected by the mutations. Deletion of cytoplasmic domain sequences of KL did not affect dimerization of KL. In contrast, dimerization of the Sl17H protein was reduced substantially. In addition, we have characterized the hematopoietic cell compartment in Sl17H mutant mice. The Sl17H mutation has only minor effects on hematopoiesis. Tissue and peritoneal mast cell numbers were reduced in mutant mice as well as in myeloid progenitors. Interestingly, long-term bone marrow cultures from Sl17H mice did not sustain the long-term production of hematopoietic cells. In addition, homing of normal hematopoietic progenitors to the spleen of irradiated Sl17H/Sl17H recipient mice was diminished in transplantation experiments, providing evidence for a role of Kit in homing or lodging. These results demonstrate that the membrane forms of KL exist as homodimers on the cell surface and that dimerization may play an important role in KL/Kit-mediated juxtacrine signaling.
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PMID:Role of dimerization of the membrane-associated growth factor kit ligand in juxtacrine signaling: the Sl17H mutation affects dimerization and stability-phenotypes in hematopoiesis. 956 37


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