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PubMed1987

Formation of mast-cell colonies in methylcellulose by mouse skin cells and development of mucosal-like mast cells from the cloned cells in the gastric mucosa of W/Wv mice.

Connective tissue-type mast cells, other than those located in the serosal cavity, are fixed in the tissues. For study of the differentiation processes of mast cells in connective tissue, an in vitro method for producing mast-cell colonies is required. The authors enzymatically dispersed the cells from the skin of either neonatal or adult mice and plated them in methylcellulose containing pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM). More than 97% of the colonies that developed consisted of mast cells alone. The clonal nature of the mast-cell colonies was determined by using the giant granules of C57BL/6-bgJ/bgJ mice as a marker: even when a mixture of skin cells from C57BL/6-bgJ/bgJ and C57BL/6-+/+ mice was plated, most of the resulting colonies consisted of either bgJ/bgJ-type mast cells alone or +/+-type mast cells alone. In spite of depletion of T-cell-derived factors, concentrations of mast cells and mast cell colony-forming units (CFU-Mast) in the skin of nude athymic mice are normal. However, PWM-SCM was necessary for in vitro development of mast-cell colonies from the skin of nude mice. The concentration of CFU-Mast in the skin of genetically mast-cell-deficient WBB6F1-W/Wv mice was negligible when compared with the value observed in the skin of control WBB6F1-+/+ mice. Individual mast-cell colonies derived from the skin of neonatal WBB6F1-+/+ mice were lifted from the methylcellulose, and cells from each colony were injected into the wall of the glandular stomach and the skin of WBB6F1-W/Wv mice. Most of the mast cell that appeared at the skin injection sites of the WBB6F1-W/Wv mice stained with berberine sulfate, indicating that they contained heparin. In contrast, the mast cells that appeared in the stomach mucosa of the recipient WBB6F1-W/Wv mice did not stain. This suggests that CFU-Mast located in the skin have not been committed to the connective tissue type. The present method may be useful for investigation of the mechanisms of mast-cell differentiation in connective tissue other than the serosal cavity.

Aging↗
PubMed1998

Isolation of human conjunctival mast cells and epithelial cells: tumor necrosis factor-alpha from mast cells affects intercellular adhesion molecule 1 expression on epithelial cells.

PURPOSE: To isolate and purify mast cells and epithelial cells from human cadaveric donor conjunctival tissue and to characterize interactions between these cell types in vitro. METHODS: Monodispersed cell suspensions obtained by enzymatic digestion of conjunctival tissue were applied to a single-density Percoll gradient. Epithelial cells obtained from the top layer of the gradient were cultured to confluence. Mast cells obtained from the pellet were equilibrated in culture medium and further purified using a two-step Percoll gradient. Using reverse transcription-polymerase chain reaction (RT-PCR), RNA from the purified mast cell preparation was probed for tumor necrosis factor-alpha (TNF alpha) message. Fluorescence activated cell sorting (FACS) analysis of intracellular immunostained mast cells was used to detect the TNF alpha protein. An examination for intercellular adhesion molecule 1 (ICAM-1) on epithelial cells was performed after 24-hour incubations with either recombinant TNF alpha supernatants from calcium ionophore A23187 (CaI)-stimulated mast cells or appropriate controls using FACS analysis. RESULTS: Highly purified human conjunctival mast cells and epithelial cells (each > 95%) were obtained from human cadaveric donor tissue. RT-PCR analysis of purified mast cell RNA revealed the expression of TNF alpha mRNA. An evaluation of mast cells for intracellular protein demonstrated positive staining for tryptase and TNF alpha. ICAM-1 was found on purified epithelial cells, and incubation of epithelial cell monolayers with supernatants from Cal-stimulated mast cells resulted in upregulation of this receptor. This upregulation was blocked by incubation with TNF alpha-neutralizing antibody. CONCLUSIONS: This work provides the methods for isolating and purifying mast cells and epithelial cells from human donor tissue and the opportunity for studying mechanisms of conjunctival inflammation by evaluating the interactions between these cells.

Calcimycin↗
PubMed1986

The bone marrow in urticaria pigmentosa and systemic mastocytosis. Cell composition and mast cell density in relation to urinary excretion of tele-methylimidazoleacetic acid.

The bone marrow sections from five normal subjects and 18 patients with mastocytosis were examined to establish criteria to distinguish urticaria pigmentosa from systemic mastocytosis. Nine patients had increased numbers of mast cells in bone marrow sections stained with a long toluidine blue staining technique specific for mast cells, whereas five patients exhibited increased numbers of mast cells on May-Grünwald-Giemsa-stained smears of bone marrow. A positive correlation between the number of mast cells in sections of the bone marrow and the urinary excretion of the main histamine metabolite tele-methylimidazoleacetic acid was found. In ten of the examined bone marrow specimens, focal lesions containing mast cells, lymphocytes, and eosinophils appeared. The presence of these focal lesions together with either an increased number of mast cells in bone marrow sections and/or increased urinary excretion of telemethylimidazoleacetic acid is considered diagnostic of systemic mastocytosis. No patient exhibited myeloproliferative condition or other major hematologic abnormality.

Adult↗
PubMed1986

Characterization of primate bronchoalveolar mast cells. II. Inhibition of histamine, LTC4, and PGD2 release from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells.

As described in the preceding companion paper, bronchoalveolar lavage (BAL) of the primate Macaca arctoides infected with the nematode Ascaris suum yields a population of cells containing a high proportion of mast cells (21%). Nedocromil sodium, a new drug undergoing clinical evaluation for the treatment of reversible obstructive airways disease, inhibited the release of histamine, LTC4, and PGD2 from these cells challenged with antigen (with IC30 values of 2.1 X 10(-6) M, 2.3 X 10(-6) M, and 1.9 X 10(-6) M, respectively) and with anti-human IgE (IC30 values of 4.7 X 10(-6) M, 1.3 X 10(-6) M, and 1.3 X 10(-6) M, respectively). Cromolyn sodium was essentially inactive. Histamine release from rat peritoneal mast cells induced by anti-rat IgE was, however, inhibited by both nedocromil sodium and cromolyn sodium with IC30 values of 1.1 X 10(-6) M and 5.5 X 10(-7) M, respectively. Both compounds induce phosphorylation of a 78,000 m.w. protein in the rat peritoneal mast cell in the absence of any stimulus at the same concentrations as those required to inhibit histamine release stimulated by anti-IgE. This event may be part of a feedback mechanism to limit degranulation. Nedocromil sodium and cromolyn sodium were equipotent in their ability to inhibit anti-IgE-induced histamine release from rat peritoneal mast cells, but differed markedly in their ability to inhibit histamine release from macaque BAL cells.

Animals↗
PubMed1994

Differential expression of mast cell growth factor receptor (c-kit) by peritoneal connective tissue-type mast cells and tissue culture-derived mast cells.

The peritoneal cavity of the mouse is a major source of connective tissue-type mast cells (CTMCs). Flow cytometric analysis using biotinylated recombinant murine mast cell growth factor (rMuMGF) showed that 1 to 3% of the cells in the peritoneal cavity exhibited MGF receptor (MGFR) (or c-kit). CTMCs were the only cell types expressing MGFR in the peritoneal cavity, and every one of them expressed MGFR. More than half the peritoneal CTMCs retained the potential to proliferate in the presence of recombinant murine interleukin 3 (rMuIL-3), rMuIL-4, and rMuMGF and gave rise to pure, alcian blue-positive "mast cells," which actively expressed c-kit transcripts and MGFR. Flow cytometric analysis and receptor assay carried out at 4 degrees C showed that the number of MGFRs on culture-derived mast cells (CDMCs) was one-third that of peritoneal CTMCs (6 x 10(4) vs. 1.8 x 10(5) MGFR/cell). At 37 degrees C, the total number of membrane MGFRs detected in CDMC was two to three times more than that detected at 4 degrees C, indicating that nearly 70% of total MGFR in CDMCs, compared with only 40% in peritoneal CTMCs, existed as "cryptic sites" unable to interact with exogenous ligand at 4 degrees C. Thus, diminished expression of MGFR is one of the phenotypic characteristics associated with CDMCs.

Animals↗
PubMed2006

Beta-adrenoceptor-mediated inhibition of mediator release from human peripheral blood-derived mast cells.

1. Mast cells cultured from human peripheral blood have been used as a cell model for functional studies of human mast cells, particularly human lung mast cells. However, the beta-adrenoceptor subtype expressed by these cultured cells has not been identified. The aim of the present study was to characterize pharmacologically the beta-adrenoceptors involved in the suppression of IgE-mediated release of mediators, including histamine, prostaglandin (PG) D2 and leukotriene (LT) C4 from cultured mast cells. 2. Mast cells were cultured from mast cell progenitors isolated from peripheral blood in the presence of 200 ng/mL stem cell factor and 50 ng/mL interleukin-6. Mast cells were sensitized with human myeloma IgE, treated with beta-adrenoceptor agonists or antagonist and then challenged with anti-human IgE. The release of histamine, PGD2 and LTC4 from mast cells was determined. 3. Both isoprenaline and salbutamol inhibited anti-IgE-induced release of histamine, PGD2 and LTC4 from cultured mast cells in a dose-dependent manner. Isoprenaline was a more potent inhibitor than salbutamol. The pD2 values for the inhibition of the release of histamine, PGD2 and LTC4 were 7.37 +/- 0.12, 8.38 +/- 0.23, 8.85 +/- 0.23, respectively, for isoprenaline and 6.96 +/- 0.12, 7.65 +/- 0.36, 7.91 +/- 0.64, respectively, for salbutamol. The selective beta3-adrenoceptor agonist BRL-37344 failed to affect anti-IgE-induced histamine release from cultured mast cells. 4. The selective beta2-adrenoceptor antagonist ICI 118 551 (108 mol/L) strongly reversed the concentration-dependent suppression of histamine release by isoprenaline and salbutamol; however, the selective beta1-adrenoceptor antagonist atenolol (106 mol/L) did not have any effect. 5. These results indicate that both isoprenaline and salbutamol act at beta2-adrenoceptors to suppress IgE-mediated mediator release from cultured human mast cells.

Adrenergic beta-Agonists↗
PubMed2005

CD34 and CD43 inhibit mast cell adhesion and are required for optimal mast cell reconstitution.

CD34 is a cell-surface sialomucin expressed by hematopoietic stem cells (HSC), mast cells, and vascular endothelia. Despite its popularity as an HSC marker, the function of CD34 on hematopoietic cells remains enigmatic. Here, we have addressed this issue by examining the behavior of mutant mast cells lacking CD34, the related sialomucin, CD43, or both molecules. Loss of these molecules leads to a gene-dose-dependent increase in mast cell homotypic aggregation with CD34/CD43KOs > CD43KO > CD34KO > wild-type. Importantly, reexpression of CD34 or CD43 in these cells caused reversal of this phenotype. Furthermore, we find that loss of these sialomucins prevents mast cell repopulation and hematopoietic precursor reconstitution in vivo. Our data provide clear-cut evidence for a hematopoietic function for CD34 and suggest that it acts as a negative regulator of cell adhesion.

Animals↗
PubMed2003

alpha-Melanocyte-stimulating hormone induces cell death in mast cells: involvement of NF-kappaB.

Mast cells play a major role in the initiation of inflammation and allergic reactions. As cell numbers are tightly controlled by the interplay of factors affecting cell proliferation, development, and death the regulation of mast cell number may be important. Melanocyte-stimulating hormone inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that the alpha-melanocyte-stimulating hormone (alpha-MSH) inhibited endotoxin-mediated nuclear transcription factor kappaB (NF-kappaB) activation in different cells correlated with the expression of alpha-MSH receptors. We have also found for the first time that it induces cell death alone or in endotoxin-stimulated mast cells. alpha-MSH-mediated apoptosis was not observed in NF-kappaB overexpressed cells. The inhibitory effect of alpha-MSH was mediated through generation of cAMP, as inhibitors of adenylate cyclase and of protein kinase A reversed its inhibitory effect. Overall, our results suggest that NF-kappaB is the key molecule involved in alpha-MSH-mediated cell death and this may help to regulate mast cell-mediated inflammation.

Animals↗
PubMed2005

Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses.

Bruton's tyrosine kinase (Btk) is thought to positively regulate mast cell activation, implying a role in allergic responses. We have compared acute and late phase allergic airway reactions in mice lacking either Btk or interleukin-2-inducible T cell kinase (Itk), another Tec kinase expressed in mast cells. Btk(-/-) mice showed minor protection against allergic symptoms when challenged with allergen via the airways. In sharp contrast, both acute and late phase inflammatory allergic responses were markedly reduced in Itk(-/-) mice. Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1. The degranulation defect was confirmed in DNP-conjugated human serum albumin-challenged mice passively sensitized with anti-DNP IgE antibodies, and was also observed after direct G-protein stimulation with the mast cell secretagogue c48/80. Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice. Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions.

Acute Disease↗
PubMed1990

Neurogenic inflammation, vascular permeability, and mast cells. II. Additional evidence indicating that mast cells are not involved in neurogenic inflammation.

Activation of cutaneous sensory nerves induces vasodilatation and vascular permeability, i.e., neurogenic inflammation. We examined the histology and possible mast cell involvement in cutaneous neurogenic inflammation induced by electrical nerve stimulation (ENS). Three lines of evidence indicated that mast cells were not involved in rodent cutaneous neurogenic inflammation induced by electrical stimulation of the saphenous nerve. 1) Most mast cells (86.5% of all mast cells in the dorsal skin of the paw) were found in the deep dermis, whereas vessels developing increased vascular permeability after nerve stimulation (visualized with the supravital dye Monastral blue B, a macro-molecular tracer) were localized predominantly in the superficial dermis. By contrast, i.v. substance P, which also causes increased cutaneous vascular permeability, predominantly caused deeper vessels to leak. As analyzed by electron microscopy, the vessels that developed permeability in response to nerve stimulation, and were thereby stained with Monastral blue B, were found to be exclusively postcapillary venules. 2) Disodium cromoglycate (DSCG), a mast cell stabilizing compound, inhibited the cutaneous vascular permeability induced by intradermal injections of anti-IgE in a dose-dependent manner. By contrast, vascular permeability induced by ENS was not influenced by disodium cromoglycate treatment. 3) ENS and i.v. substance P both induced cutaneous vascular permeability in mast cell-deficient W/Wv mice, despite the fact that their skin contained only 4.7% of the mast cells present in their normal +/+ litter mates. The magnitude of ENS-induced vascular permeability responses in W/Wv mice were similar to control +/+ and BALB/c mice. This study supports our earlier observations suggesting that mast cell activation is not essential for the initial, vascular permeability phase of neurogenic inflammation in rodent skin.

Animals↗
PubMed2002

The role of SHIP in mast cell degranulation and IgE-induced mast cell survival.

Atopic disorders are on the increase in the Western world and are due, at least in part, to an overactive mast cell response. A better understanding of the intracellular signalling pathways that regulate both mast cell degranulation and the secretion of arachidonic acid metabolites and inflammatory cytokines could help in the treatment of these disorders. The src homology 2-containing inositol-polyphosphate 5'-phosphatase, SHIP, has been shown to be a key 'gatekeeper' of mast cell degranulation. SHIP prevents degranulation from occuring when IgE alone binds to the high-affinity receptor for IgE (FcvarepsilonR1), SHIP restrains it when IgE-bound FcvarepsilonR1 are engaged by multivalent allergens, and SHIP inhibits it when an IgG against the same allergen co-clusters the inhibitory low-affinity receptor for IgG (FcgammaRIIB) with the IgE receptor. SHIP acts as a negative regulator of degranulation by hydrolyzing phosphatidylinositol-3,4,5-trisphosphate, a second messenger generated in activated cells by phosphatidylinositol 3-kinase. Our finding that binding of only IgE to the FcvarepsilonR1 of SHIP-deficient mast cells results in massive degranulation, led us to investigate the signalling pathways that are triggered in normal murine bone marrow-derived mast cells by monomeric IgE. We report here that monomeric IgE activates signalling pathways resulting in mast cell survival, without stimulating degranulation or proliferation. These studies demonstrate that mast cell sensitization by IgE is an active rather than a passive process.

Animals↗
PubMed2000

Canine extracutaneous mast-cell tumours consisting of connective tissue mast cells.

Two cases of canine extracutaneous mast-cell tumours were encountered, originating from the mucosa of either the oral cavity or the small intestine. The dogs had no neoplasms in the skin. Immunohistochemical and ultrastructural studies demonstrated that the neoplastic cells had the features of connective tissue mast cells. It would seem, therefore, that at least some extracutaneous forms of the neoplasm originate from connective tissue mast cells. Heparin was a useful cytological marker to diagnose this type of mast-cell tumour.

Animals↗
PubMed1990

Specific high-affinity receptors for interferon-gamma on mouse bone marrow-derived mast cells: inhibitory effect of interferon-gamma on mast cell precursors.

Cultured mast cells derived from murine bone marrow were investigated for the presence of specific interferon-gamma (IFN-gamma) receptors, and for the effects of IFN-gamma on mast cell proliferation. 125I-labeled recombinant IFN-gamma (125I-Mu-rIFN-gamma) was shown to bind to high-affinity receptors on these cells. Scatchard analysis of binding data indicated the presence of about 500 homogeneous binding sites per cell, with an apparent equilibrium dissociation constant of 3 X 10(-10) M. The binding of 125I-Mu-rIFN-gamma to mast cells was inhibited by unlabeled Mu-rIFN-gamma but not by unlabeled Mu-IFN-alpha/beta. Cross-linking of 125I-Mu-rIFN-gamma to mast cell membrane proteins using a cross-linking agent yielded a predominant complex of 100 +/- 10 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography which most likely represents the IFN-gamma-receptor complex. To assess the biological significance of these receptors, we studied the effects of Mu-rIFN-gamma on mast cell proliferation, which was markedly inhibited in mast cell precursors but not in mature mast cells. These in vitro results are in agreement with the antiproliferative effect of IFN-gamma previously reported for other hematopoietic progenitors, and suggest that IFN-gamma could find its application in the treatment of human systemic mastocytosis.

Animals↗
PubMed1986

Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities.

A cDNA sequence coding for a unique mouse interleukin that expresses B-cell-, T-cell, and mast-cell-stimulating activities has been isolated from a mouse helper T-cell cDNA library. The library, constructed in the pcD expression vector, was screened by transfecting COS monkey cells with DNA pools to express the products encoded by full-length cDNA inserts. By assaying the transfected cell supernatants, we identified clones encoding a factor that stimulates T-cell and mast cell lines. This factor also induces Ia expression on resting B cells and enhances IgG1 and IgE production by B cells, two properties of B-cell-stimulatory factor 1. The DNA sequence codes for a polypeptide of 140 amino acid residues including a putative signal peptide. These results demonstrate that a single cDNA clone distinct from interleukin 2 and interleukin 3 encodes a polypeptide with multiple biological activities.

Amino Acid Sequence↗
PubMed1986

Development of mucosal mast cells after injection of a single connective tissue-type mast cell in the stomach mucosa of genetically mast cell-deficient W/Wv mice.

Mast cells may be classified into at least two phenotypically distinct populations: connective tissue-type mast cells (CTMC) and mucosal mast cells (MMC). Mast cells in the peritoneal cavity of mice are typical CTMC, whereas mast cells in the mucosa of the stomach show morphologic characteristics of MMC. We investigated whether CTMC may change to MMC. A single peritoneal mast cell of WBB6F1-+/+ mice was identified under the phase-contrast microscope, picked up with the micromanipulator, and injected into the stomach wall of genetically mast cell-deficient WBB6F1-W/Wv mice. The cells with histochemical and electron microscopical features of MMC developed in the mucosa, and those with histochemical features of CTMC in the muscularis propria. This directly demonstrates that a certain proportion of CTMC may function as a bipotent precursor for both MMC and CTMC.

Animals↗
PubMed1984

Proliferation of peritoneal mast cells in the skin of W/Wv mice that genetically lack mast cells.

Presence of mast cell precursors in the mouse peritoneal cavity was demonstrated, and the precursors were characterized. When a cell suspension, containing mast cell precursor(s), was directly injected into the skin of genetically mast cell-deficient WBB6F1 (WB X C57BL/6)-W/Wv mice, a cluster composed of approximately 2,000 mast cells appeared at the injection site. By determining the proportion of injection sites at which the mast cell cluster appeared, the concentration of mast cell precursors can be calculated by limiting dilution analysis. The concentration in the peritoneal cavity was about five times as great as the concentration in the bone marrow. Although peritoneal mast cell precursors were shown to originate from the bone marrow, physical characterization revealed that the peritoneal precursors differed from the marrow precursors. The peritoneal precursors were less susceptible to irradiation than the marrow precursors; the former were heavier than the latter. When a 95% pure mast cell suspension was prepared from the peritoneal cells by the removal of phagocytes and the density gradient centrifugation, 1 out of 16 cells had the potentiality to make a mast cell cluster in the skin of the W/Wv mice. Moreover, when a single mast cell was identified under the phase contrast microscope and picked up with the micromanipulator, 1 out of 17 mast cells made the cluster. This indicated that some peritoneal mast cells kept extensive proliferative potentiality even after morphological differentiation. In other words, some peritoneal mast cells themselves may function as the committed precursors.

Animals↗