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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 have been implicated in a wide variety of biological responses, but identifying the nature and importance of the mast cell's specific contributions to these reactions has been difficult. W/Wv mice have mutations affecting the c-kit tyrosine kinase receptor which is encoded at the W locus and which is necessary for normal mast cell development. In W/Wv mice, the cells which ordinarily give rise to normal mast cell populations do not adequately respond to a major migration, survival, proliferation and maturation factor expressed in the microenvironments where mast cells ordinarily develop: the c-kit receptor ligand, SCF. As a result, W/Wv mice virtually lack tissue mast cells. However, adoptive transfer to W/Wv mice of immature mast cells derived in vitro from the bone marrow cells of the congenic normal (+/+) mice selectively repairs the mast cell deficiency of the W/Wv recipients. These "mast cell knock-in" mice can be used to analyze the expression of biological responses in tissues which differ only because they do or do not contain populations of mast cells. This approach permits identification and quantification of the specific contributions of the mast cell to biological responses expressed in the skin, gastrointestinal tract and other anatomical sites, and also greatly facilitates analysis of the mechanisms by which mast cells influence these responses.
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PMID:Analyzing mast cell development and function using mice carrying mutations at W/c-kit or Sl/MGF (SCF) loci. 128 Sep 35

Mutant mice of mi/mi genotype are osteopetrotic and deficient in tissue mast cells due to a defect in osteoclasts and mast cells. In an effort to further understand the mechanisms behind why mi/mi mouse-derived cultured mast cells (mi/mi-CMC) responded to interleukin-3 (IL-3), but not to the proliferative stimuli presented by fibroblasts, mi/mi-CMC and congenic normal (+/+) mouse-derived CMC (+/+-CMC), both of which expressed the phenotypic characteristics of immature mast cells, were cocultured with Swiss albino/3T3 fibroblasts in a medium containing IL-3. In the in vitro CMC/fibroblast coculture, mi/mi-CMC did not acquire the phenotypes of connective tissue-type mast cells (CTMC), while +/+-CMC did. In addition, attachment of mi/mi-CMC to the fibroblasts was found to be significantly lower than that of +/+-CMC. Because the interaction of c-kit product with its ligand (stem cell factor [SCF]) is known to play an important role not only in proliferation and differentiation of mast cells but also in attachment of CMC to fibroblasts, the expression and function of c-kit were investigated in mi/mi-CMC and +/+-CMC. Recombinant rat SCF (rrSCF164) induced a dose-dependent proliferation of +/+-CMC. Also, rrSCF164 induced +/+-CMC to acquire the phenotypes of CTMC in the medium containing IL-3. By contrast, rrSCF164 did not stimulate the proliferation of mi/mi-CMC nor induce a phenotypic change of the cells from immature mast cells to mature, CTMC-like mast cells. Immunoblotting with antiphosphotyrosine antibody showed that rrSCF164 induced considerable tyrosine phosphorylation of 145- to 165-Kd protein, the product of c-kit, in +/+-CMC, whereas tyrosine phosphorylation of the protein was barely detectable in mi/mi-CMC. Northern blot and flow cytometry analyses showed that mi/mi-CMC expressed much less c-kit at both protein and message levels than +/+-CMC. Further, mi/mi-CMC were found to differ from +/+-CMC in the expression of mouse mast cell protease-6 (MMCP-6) and MMCP-2 messenger RNA transcripts. These results suggest that the gene product of the mi locus may be important in regulating the expression of gene products such as c-kit, and that mast cell deficiency of mi/mi mice appears to be due, at least in part, to impaired signaling through the c-kit receptor because of the low c-kit expression.
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PMID:Low c-kit expression of cultured mast cells of mi/mi genotype may be involved in their defective responses to fibroblasts that express the ligand for c-kit. 138 28

The high-affinity receptor for IgE, Fc epsilon RI, represents the major cell surface structure through which mast cells express immunologically specific secretory function. By contrast, the stem cell factor receptor (SCFR), which is encoded by c-kit, is essential for normal mast cell development. The signaling pathways initiated by the stimulation of mast cells through the Fc epsilon RI, which lacks intrinsic kinase activity, and the SCFR, a member of the receptor tyrosine kinase family, generally have been regarded to be distinct. We report here that mouse mast cells stimulated either with SCF or with IgE and specific antigen exhibit a remarkably similar pattern of activation of mitogen-activated protein kinases (MAPK), 90 kDa-S6 kinases (pp90rsk), and pp70-S6 kinases (pp70-S6K). These results indicate that all three families of protein kinases are associated with the cell surface receptor-dependent activation of secretion, as well as proliferation, in mast cells. We also show that the immunosuppressant rapamycin, but not FK506, can inhibit both SCF-dependent pp70-S6 kinase activation and SCF-dependent proliferation in mouse mast cells, without suppressing IgE- and antigen-dependent mediator release. These findings suggest that the activation of pp70-S6 kinase represents an important link in the stimulation of cell proliferation by SCF. Our results also indicate that the intracellular signaling pathways initiated by stimulation of mast cells through the Fc epsilon RI or the SCFR exhibit more overlap than has previously been appreciated.
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PMID:Activation of MAP kinases, pp90rsk and pp70-S6 kinases in mouse mast cells by signaling through the c-kit receptor tyrosine kinase or Fc epsilon RI: rapamycin inhibits activation of pp70-S6 kinase and proliferation in mouse mast cells. 750 92

The clinical symptoms of allergy are caused by cellular (IgE-triggered) responses to an allergen. Effector cells of allergy include eosinophil and basophil granulocytes, as well as tissue mast cells. Growth and accumulation, as well as IgE-dependent and independent functions of these cells are regulated by distinct proteohormones and peptides. The hemopoietic cytokines IL-3 (interleukin-3), IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) are involved in the regulation of basophils (and eosinophils), whereas the ligand for c-kit, SCF (stem cell factor) is a mast cell-specific agonist. Basophils and mast cells express high-affinity IgE-binding sites. Allergen binding to IgE on mast cells and basophils, and consecutive cross-linking of IgE receptors is followed by production and/or secretion of inflammatory mediator substances. Specific activation and deactivation of mast cells/basophils in vitro has been demonstrated by use of recombinant cytokines and allergens, and specific haptens or by use of novel drugs, and should lead to epitope-specific diagnosis and better management of allergic diseases in the future.
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PMID:[Effector cells in allergy: biological principles and new pharmacologic concepts]. 750 62

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in mast cell growth and differentiation. In a human mast cell leukemia cell line (HMC-1), KitR was found to be constitutively phosphorylated on tyrosine, activated and associated with phosphatidylinositol 3-kinase (P13K) in the absence of autocrine production of SCF. Sequencing of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations in codon 560 and codon 816, resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp, respectively. Murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in cells of a human embryonic kidney cell line (293T). In the transfected cells, KitR (Gly-559 + Val-814) and KitR (Val-814) were strikingly phosphorylated on tyrosine and activated in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (Gly-559) or wild-type KitR was modest or little, respectively. These results suggest that constitutive activation of KitR in HMC-1 results from the activating mutations of c-kit gene, and raise the possibility that the activating mutations, particularly at codon 814 of murine c-kit or at codon 816 of human c-kit, may participate in oncogenesis of mast cells.
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PMID:Activating mutations of the c-kit proto-oncogene in a human mast cell leukemia cell line. 751 80

The mast cell is one of the major effector cells in inflammatory reactions and can be found in most tissues throughout the body. During inflammation, an increase in the number of mast cells can be seen, e.g., in the intraepithelial cell layer after a provoked allergic reaction. Such accumulation probably requires directed migration of mature mast cells or their precursors. To study the migration of human mast cells we used as a model the human mast cell line, HMC-1, and stem cell factor-dependent (also referred to as mast cell growth factor or Kit ligand) cord blood-derived mast cells. The results show that stem cell factor is a potent chemotactic factor for human mast cells in vitro. The chemotactic response to SCF was found to be dose dependent, reaching a maximum at 50 ng/ml. The activity of SCF could be blocked by anti-SCF Abs. We also tested the effect of different intercrines, i.e., IL-8, MIP-1 alpha, MIP-1 beta, RANTES, and MCAF (also referred to as monocyte chemotactic protein 1), on human mast cell migration. Only RANTES was chemotactic for in vitro-developed mast cells. None of the tested intercrines induced migration of HMC-1 cells. For migration, the mast cells were dependent on binding to an extracellular matrix protein. Thus, coating of the filters with fibronectin was required, whereas collagen or laminin did not promote migration. Adhesion of HMC-1 cells to fibronectin could also be shown in an adhesion assay. In addition, expression of receptors for fibronectin could be detected on the surface of the mast cells. These results show that SCF is not only a growth and differentiation factor for human mast cells in vitro but also a potent chemoattractant for such cells.
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PMID:Stem cell factor is a chemotactic factor for human mast cells. 752 4

We have isolated and characterized the human cardiac mast cell (CMC) and compared this novel mast cell (MC type with MC obtained from uterus, skin, and lung. Heart tissue was obtained from 14 patients with cardiomyopathy (CMP, heart transplantation). CMC were isolated by enzymatic digestion using collagenase, pronase-E, hyaluronidase, and DNAse. Substantial amounts of CMC (0.5% to 1.5% of isolated cells) were found in the atrial appendages but not in ventricular digests or other sites of the heart (< 0.1%). In situ staining of atrial tissue revealed the presence of CMC in the myocardium (2.16 +/- 0.7 MC/mm2), endocardium (2.24 +/- 0.9 MC/mm2), and epicardium. As assessed by combined toluidine blue/immunofluorescence staining with monoclonal antibodies (MoAbs), isolated CMC expressed surface IgE, the receptor for stem cell factor (c-kit receptor/CD117), the p24 antigen (CD9), the Pgp-1 homing receptor (CD44), the pan leukocyte antigen (CD45), and the ICAM-1 antigen (CD54). CMC were not recognized by MoAbs to lymphocyte function associated antigen 2 (LFA-2; CD2), T-cell receptor (TcR; CD3), T4 antigen (CD4), LFA-1 alpha-chain (CD11a), C3biR alpha-chain (CD11b), CR4 alpha-chain (CD11c), LPS-R related Ag (CD14), 3-FAL/x-hapten (CD15), Fc gamma RIII (CD16), lactosylceramid (CDw17), the B-cell antigen CD19, or CR1 (CD35). In situ expression of leukocyte antigens on CMC was demonstrable by indirect immunoperoxidase staining technique and double-labeling immunohistochemistry. Almost all CMC (90%) reacted with MoAbs against tryptase and chymase and thus were MCTC. Cardiac mast cells were also stained by the heparin-binding dye Berberine sulfate and expressed measurable amounts of histamine (4.6 +/- 1.4 pg per cell). Cross linking of either IgE receptor or SCF receptor (c-kit) on CMC resulted in histamine secretion (non-specific release: < 6% of total histamine, alpha IgE induced: 12% to 52%; SCF-induced release: 9% to 18%), whereas neither substance P (a skin MC agonist) nor the basophil agonist FMLP showed an effect on CMC. Together, the CMC is an MCTC primarily located in the appendage of the atrium. This novel type of MC exhibits surface membrane antigen and functional properties similar to those of lung and uterus MC.
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PMID:The human cardiac mast cell: localization, isolation, phenotype, and functional characterization. 752 50

We examined the expression of Fc epsilon-RI and Fc gamma-RII/III on mouse bone marrow cells enriched for hematopoietic progenitors including mast cell progenitors. Bone marrow cells were depleted of mature hematopoietic lineages and a primitive population of cells that express the proto-oncogene c-kit (KIT+ lineage- cells) was isolated. KIT+ lineage- cells stain positively using the Ab 2.4G2, indicating surface expression of Fc gamma-RII and/or Fc gamma-RIII. Fluorescent staining of intracytoplasmic domains of Fc gamma-RII and Fc gamma-RIII revealed that these cells express primarily Fc gamma-RII on their surface. KIT+ lineage- cells did express Fc gamma RIII alpha-chain protein, but predominately in the nuclear/perinuclear area. We could not detect surface expression of Fc epsilon-RI by KIT+ lineage- cells, although a heterogeneous population of KIT- cells does bind IgE with high affinity and may reflect cells of the basophilic lineage. KIT+ lineage- cells cultured with SCF and IL-3 generate numerous mast cells, whereas equivalent numbers of KIT- cells or naive bone marrow cells do not. In these cultures, surface expression of Fc epsilon-RI is detected on a small number of cells by day 3 of culture with increased surface expression levels correlating roughly with metachromatic granule formation. The fact that Fc gamma-RIII and Fc epsilon-RI are not expressed on the cell surface of KIT+ lineage- cells but appear later in hematopoietic development makes it unlikely that these receptors influence early hematopoietic differentiation. The role that might justify such a complete surface expression of Fc gamma-RII by bone marrow progenitors remains to be identified.
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PMID:Murine KIT+ lineage- bone marrow progenitors express Fc gamma-RII but do not express Fc epsilon-RI until mast cell granule formation. 752 15

Human fetal liver cells cultured in the presence of recombinant human stem cell factor (rhuSCF) give rise to highly purified mast cell populations. This study examined the effect of steroid hormones on mast cell differentiation. Dispersed fetal liver cells cultured in the presence of rhuSCF at 50 ng/ml and in the presence or absence of various steroid hormones for 4 weeks, were analysed for the presence of mast cells by metachromatic staining with toluidine blue, by immunohistochemistry with a monoclonal antibody against tryptase, and by immunofluorescent flow cytometry with a monoclonal antibody against Kit. Dexamethasone added to the cultures at day 0 resulted in a dose-dependent inhibition of rhuSCF-induced mast cell differentiation with > 85% inhibition seen at a dose of 10(-6) M. A similar effect was seen with hydrocortisone, but not with oestradiol or progesterone. The addition of dexamethasone resulted in decreased DNA synthesis in 14-day-old cultured cells, as assessed by incorporation of bromodeoxyuridine. Addition of dexamethasone to 3-week-old SCF-dependent fetal liver mast cells had no significant effect on mast cell survival. Removal of dexamethasone after 3 weeks of culture with SCF did not result in mast cell development. Thus, dexamethasone inhibits SCF-induced development of mast cells from fetal liver cells, but shows no appreciable effect on developed mast cells.
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PMID:Dexamethasone inhibits the development of mast cells from dispersed human fetal liver cells cultured in the presence of recombinant human stem cell factor. 753 66

Chemokines are proinflammatory peptides regulating the functions of various hematopoietic cells. We have analyzed the effects of seven recombinant human (rh) chemokines (MCAF, RANTES, MIP-1 alpha, MIP-1 beta, IL-8, GRO, and IP-10) on the growth and function of human basophils and mast cells. We found that MCAF, but not RANTES, MIP-1 alpha, MIP-1 beta, IL-8, GRO, or IP-10, causes direct and dose-dependent histamine release from basophils (MCAF, 5 micrograms/ml: 26.9 +/- 3.4%; other chemokines: < 5% of total histamine). An increased (2.1 to 3.5-fold) response to MCAF was obtained when basophils were preincubated with rh interleukin-3 (100 units/ml). Moreover, IL-3-primed basophils became responsive to physiologic concentrations (< 1 microgram/ml) of MCAF, IL-8, and RANTES. None of the chemokines tested was able to induce histamine secretion in mast cells obtained from lung (n = 2), skin (n = 1), uterus (n = 3), or tonsils (n = 3), even when cells had been preincubated with the mast cell agonist SCF. The chemokines also failed to modulate the expression of activation antigens (CD11b/C3biR, CD25/IL-2R beta, CD63, IL-3R alpha, CD117/c-kit) on the mast cell line HMC-1 or the basophil cell line KU-812 and were unable to induce differentiation of basophils or mast cells in culture. Together, our results show that basophils respond to rhIL-8, rhMCAF, and rhRANTES and that, unlike human basophils, human mast cells are unresponsive to recombinant chemokines.
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PMID:Differential response of human basophils and mast cells to recombinant chemokines. 754 Dec 56


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