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PubMed1997

Mast cells.

Mast cells are found resident in tissues throughout the body, particularly in association with structures such as blood vessels and nerves, and in proximity to surfaces that interface the external environment. Mast cells are bone marrow-derived and particularly depend upon stem cell factor for their survival. Mast cells express a variety of phenotypic features within tissues as determined by the local environment. Withdrawal of required growth factors results in mast cell apoptosis. Mast cells appear to be highly engineered cells with multiple critical biological functions. They may be activated by a number of stimuli that are both Fc epsilon RI dependent and Fc epsilon RI independent. Activation through various receptors leads to distinct signaling pathways. After activation, mast cells may immediately extrude granule-associated mediators and generate lipid-derived substances that induce immediate allergic inflammation. Mast cell activation may also be followed by the synthesis of chemokines and cytokines. Cytokine and chemokine secretion, which occurs hours later, may contribute to chronic inflammation. Biological functions of mast cells appear to include a role in innate immunity, involvement in host defense mechanisms against parasitic infestations, immunomodulation of the immune system, and tissue repair and angiogenesis.

Animals↗
PubMed1986

The function and properties of human lung mast cells.

Mast cells may be recovered from human subjects by bronchoalveolar lavage. Such bronchoalveolar mast cells will release histamine in response to IgE-dependent challenge in a reaction that is dose-, time- and energy-dependent. They possess functional characteristics distinct from dispersed human lung mast cells. The percentage of mast cells within the bronchoalveolar cell population is critically dependent upon the underlying pathology. Greater numbers of mast cells may be recovered from the bronchoalveolar compartment of extrinsic asthmatics than from controls. In addition, bronchoalveolar mast cells from asthmatic subjects show an increased releasability of histamine in response to anti-IgE. Antigen challenge also leads to the release of histamine in vitro, demonstrating the potential for the antigen-specific initiation of bronchoconstriction in these subjects. Spontaneous release of histamine from bronchoalveolar mast cells of asthmatic subjects was also greater than in controls (up to 46%), a feature which may be related to non-immunological mechanisms of bronchoconstriction. Such non-immunological mechanisms have been further investigated utilising mannitol as a model of hyperosmolar histamine release. Mannitol induced a dose-dependent release of histamine from bronchoalveolar mast cells of normal subjects, and this release was significantly inhibited by sodium cromoglycate. The leukotrienes are putative major mediators of human asthma. After challenge with anti-IgE in vitro, dose-dependent release of leukotriene C4 and prostaglandin D2 occurs from the bronchoalveolar cells of normal subjects. The release of PGD2 shows significant correlation with histamine release. Lying superficially, bronchoalveolar mast cells would be readily accessible to inhaled antigen. Mediator release from such cells may be relevant to the pathogenesis of asthma.

Animals↗
PubMed2006

Bacterial activation of mast cells.

Mast cells often are found in a perivascular location but especially in mucosae, where they may response to various stimuli. They typically associate with immediate hypersensitive responses and are likely to play a critical role in host defense. In this chapter, a common airway pathogen, Moraxella catarrhalis, and a commensal bacterium, Neiserria cinerea, are used to illustrate activation of human mast cells. A human mast cell line (HMC-1) derived from a patient with mast cell leukemia was activated with varying concentrations of heat-killed bacteria. Active aggregation of bacteria over mast cell surfaces was detected by scanning electron microscopy. The activation of mast cells was analyzed by nuclear factor-kappaB (NF-kappaB) activation and cytokine production in culture supernatants. Both M. catarrhalis and N. cinerea induce mast cell activation and the secretion of two key inflammatory cytokines, interleukin-6 and MCP-1. This is accompanied by NF-kappaB activation. Direct bacterial contact with mast cells appears to be essential for this activation because neither cell-free bacterial supernatants nor bacterial lipopolysaccharide induce cytokine secretion.

Cells, Cultured↗
PubMed2006

Isolation, culture, and characterization of intestinal mast cells.

Mast cells are bone-marrow-derived tissue cells typically located at barrier sites of the body, such as skin, mucosal barriers, or blood barriers, that is, around blood vessels. This location suggests that mast cells might have a function as immunological "gate-keepers" or "watch dogs" and, indeed, some recent functional data support this idea. Mast cells derive from myeloid progenitors, but in contrast to other myeloid cells, they leave the bone marrow in an immature state; therefore, mast cells are not found in the blood under normal conditions. For full maturation, the tissue environment is necessary. Thus, mature mast cells can be only isolated from tissue such as skin or mucosal sites, which makes mast cell isolation rather complicated. Alternatively, mast cell progenitors can be isolated from the bone marrow, peripheral blood, or cord blood, which is easier but requires subsequent in vitro maturation of mast cells as far as possible using cytokines. This chapter describes a rather new technique of mast cell isolation from human intestinal mucosal tissue yielding approx 1-5 million pure and viable human mast cells suitable to perform functional and cell culture experiments.

Animals↗
PubMed1997

Human leukaemic (HMC-1) and normal skin mast cells express beta 2-integrins: characterization of beta 2-integrins and ICAM-1 on HMC-1 cells.

Mast cells are bone marrow-derived, ubiquitous connective tissue resident cells. However, their mechanisms of migration, the distribution of immature and mature cells and their interaction with other inflammatory cells are largely unclarified. Possibly, beta 2-integrins play an important role in these processes. In the present investigation, the authors studied the expression and regulation of the beta 2-integrins LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), p150,95 (CD11c/CD18) and of the LFA-1/Mac-1 counter-receptor intercellular adhesion molecule-1 (ICAM-1; CD54) on leukaemic (HMC-1 cell subclone 5C6) and on normal mature human skin mast cells. The HMC-1 cells clearly expressed CD11a, CD18 and CD54, while expression of CD11b and CD11c was low. The apparent molecular weights were 180 kDa (CD11a), 95 kDa (CD18) and 90 kDa (CD54) as determined by Western blot analysis. Phorbol myristate acetate (PMA) induced a time- and dose-dependent up-regulation of CD11a, CD11b, CD11c, CD18 and CD54 that was inhibited by cycloheximide, suggesting a dependence on de novo protein synthesis. Enhanced expression of CD11a, CD11b, CD11c and CD18 could also be confirmed at the gene level as demonstrated by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Increased expression of LFA-1/ICAM-1 in response to PMA was accompanied by strong enhancement of homotypic cell aggregation, suggesting that newly synthesized LFA-1/ICAM-1 is functionally active. In order to determine a physiologically relevant way of mast cell beta 2-integrin modulation, several cytokines and chemotactic mediators (interleukin-4, IL-4; nerve growth factor beta, NGF beta; C5a; and leukotriene B4, LTB4) were tested for their influence on adhesion molecule cell surface density. Only LTB4 was shown specifically to up-regulate CD11a and CD18, but not CD11b or CD11c. The presence of CD11a, CD11c and CD18 could be confirmed on a low percentage of normal skin mast cells by immunofluorescence, using a double staining technique. In comparison to normal skin, a significantly higher percentage of CD18+ mast cells was found in inflammatory dermatoses such as psoriasis vulgaris, atopic dermatitis and lichen planus. Therefore, mast cell beta 2-integrins possibly play an important role during homing of immature mast cells as well as during the interaction of activated mast cells with other inflammatory cells.

Base Sequence↗
PubMed2005

Buffy coat preparation is a convenient source of progenitors for culturing mature human mast cells.

Mast cells are unique immune cells that release a spectrum of chemical mediators contributing to the inflammatory symptoms of allergic disorders. Mature mast cells have recently been cultured from CD34(+) progenitors isolated from fresh umbilical cord blood and adult peripheral blood. In the current study, we investigated whether buffy coat preparations, which are readily available from blood banks, could be used as a convenient and more abundant source of progenitors for culturing human mast cells. We were able to culture a homogeneous population of human mast cells from progenitor cells isolated from human buffy coat. Morphologically, our cultured mast cells contained abundant cytoplasmic granules which stained positively using antibodies against human mast cell tryptase and, to a lesser extent, with those against human mast cell chymase. Functionally, these cultured mast cells responded to anti-human-IgE by releasing histamine in a dose-dependent manner after sensitization with human IgE. Taken together, buffy coat preparations can be a convenient source for culturing human mast cells which are predominantly tryptase positive only and express functional high-affinity IgE receptors.

Blood Cells↗
PubMed1996

Definitive characterization of rat hypothalamic mast cells.

Mast cells have previously been identified in mammalian brain by histochemistry and histamine fluorescence, particularly in the rat thalamus and hypothalamus. However, the nature of brain mast cells has continued to be questioned, especially because the electron microscopic appearance often shows secretory granule morphology distinct from that of typical connective tissue mast cells. Here we report that mast cells in the rat hypothalamus, identified based on metachromatic staining with Toluidine Blue, fluoresced after staining with berberine sulfate, indicating the presence of heparin. These cells were also positive immunohistochemically for histamine, as well as for rat mast cell protease I, an enzyme characteristically present in rat connective tissue mast cells. In addition, these same cells showed a very strong signal with in situ hybridization for immunoglobulin E binding protein messenger RNA. However, use of antibodies directed towards immunoglobulin E or its binding protein did not label any cells, which may mean either the binding protein is below the level of detection of the techniques used or that it is not expressed except in pathological conditions when the blood-brain barrier becomes permeable. At the ultrastructural level, perivascular mast cells contained numerous, intact, electron-dense granules which were labeled by gold-labeled anti-rat mast cell protease I. These results clearly demonstrate the presence of perivascular mast cells in the rat hypothalamus, where they may participate in homeostatic processes.

Animals↗
PubMed2003

Genetic evidence for convergence of c-Kit- and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells.

Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, in rheumatoid arthritis, and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanisms by which mast cells migrate to various tissues under steady state conditions or during infection or inflammation. Here, we show that activation of c-Kit by its ligand, stem cell factor (SCF), cooperates with alpha4 integrin in inducing directed migration of mast cells on fibronectin. A reduction in migration and activation of a small G protein, Rac, was observed in mast cells derived from class IA phosphoinositide-3 kinase (PI-3kinase)-deficient mice in response to SCF stimulation and in mast cells expressing the dominant-negative Rac (RacN17), as well as in mast cells deficient in the hematopoietic-specific small G protein, Rac2. In addition, a PI-3kinase inhibitor inhibited alpha4- as well as SCF-induced migration in a dose-dependent fashion. In contrast, a mitogen-activated protein kinase (MAPK) inhibitor had little effect. Consistent with the pharmacologic results, abrogating the binding of the p85alpha subunit of class IA PI-3kinase to c-Kit also resulted in inhibition of SCF-induced migration on fibronectin. These genetic and biochemical data demonstrate that both c-Kit and alpha4 integrin signaling are linked to class IA PI-3kinase and Rac pathways and regulate integrin-directed (haptotactic) migration in mast cells.

Animals↗
PubMed1992

[The phenotype of mast cells in primary adenoid liver tumours of rats and its relation to tumor cells].

Mast cells in adenoid liver tumours of 32 rats induced with nitrosomorpholine were observed ultrastructurally, and among them, some were studied immunocytochemically via immunogold techniques. Data indicated that mast cells which located in tumour tissues presented positive expression of rat mast cell protein (RMCP) II, indicating origination from the mucosal mast cells, while those in the connective tissues around tumours were largely stained negatively with either RMCP II or RMCP I antisera, with the exception of only a few cells showing positive RMCP II staining. Ultrastructural observation showed that mast cells in tumors contacted closely with the tumor cells. Membranes of the intracellular granules in these mast cells were fusing together. The content inside the granules were discharged and spread along the intercellular space between the tumor cells. There was not any lesion obtained ultrastructurally at the contacting point between the tumor cells and the mast cells. The significance of mucosal mast cells in adenoid liver tumors is briefly discussed.

Animals↗
PubMed2002

Fer kinase is required for sustained p38 kinase activation and maximal chemotaxis of activated mast cells.

Mast cells play important roles in inflammation and immunity and express the high-affinity immunoglobulin E receptor (Fc epsilon RI) and the receptor protein-tyrosine kinase Kit. Aggregation of Fc epsilon RI via antigen binding elicits signals leading to the release of preformed inflammatory mediators as well as de novo-synthesized lipid mediators and cytokines and to elevated cell adhesion and migration. Here, we report that in mouse bone marrow-derived mast cells, Fer kinase is activated downstream of activated Fc epsilon RI and activated Kit receptor, and this activation is abolished in cells homozygous for a kinase-inactivating mutation in Fer (fer(DR/DR)). Interestingly, the highly related Fps/Fes kinase is also activated upon Fc epsilon RI aggregation. This report represents the first description of a common signaling pathway activating Fer and Fps/Fes. While Fer-deficient cells showed similar activation of the Erk mitogen-activated protein (MAP) kinases, p38 MAP kinase activation was less sustained than that in wild-type cells. Although no major defects were observed in degranulation, leukotriene biosynthesis, and cytokine secretion, Fer-deficient cells displayed increased adhesion and decreased motility upon activation of Fc epsilon RI and the Kit receptor. The restoration of Fer kinase activity in fer(DR/DR) mast cells resulted in prolonged p38 kinase activation and increased antigen-mediated cell migration of sensitized mast cells. Thus, Fer is required for maximal p38 kinase activation to promote the chemotaxis of activated mast cells. Further studies with mast cells derived from fps/fes-deficient mice will be required to provide insight into the role of Fps/Fes in mast cell activation.

Animals↗
PubMed1991

Trigeminal sensory fiber stimulation induces morphological changes reflecting secretion in rat dura mater mast cells.

Mast cells are involved in allergic reactions, but may also participate in neurogenic inflammation. The morphology of mast cells in rat dura mater and tongue was evaluated by histochemistry, as well as by scanning and transmission electron microscopy following unilateral trigeminal ganglion stimulation (5 min, 5 Hz, 5 ms, and 0.02, 0.1 or 1.0 mA). Mast cells in dura and tongue of normal animals were numerous, perivascular and often in close proximity to nerve fibers. After 5 min of electrical stimulation, mast cells contralateral to the stimulation showed histochemical characteristics of normal peripheral tissue mast cells (Safranin-positive), and by electron microscopy appeared homogeneous with numerous intact electron-dense granules. On the stimulated side, however, the staining characteristics of mast cells showed changes indicating progressive intracellular loss of their granular content. In addition, the total number of stainable mast cells decreased at all three stimulus intensities, but reached significance only at 0.1 and 0.02 mA. Ultrastructural evidence of granule changes consistent with secretion were observed although degranulation was not observed until 20 min after stimulation. There were no mast cell changes after electrical trigeminal stimulation in adult rats treated as neonates with capsaicin to destroy small caliber sensory afferent axons. These results suggest that mast cells may secrete in response to electrical stimulation of trigeminal axons, possibly mediated by antidromic release of neuropeptides, and may participate in the development of neurogenic inflammation.

Animals↗
PubMed2005

Chromatin-based regulation of cytokine transcription in Th2 cells and mast cells.

Th2 cells and mast cells are major sources of IL4, IL5 and IL13, cytokines that mediate immunity against parasites and are also central players in the pathophysiology of asthma, allergy and atopic disease. We asked whether Th2 cells and mast cells, which belong to the lymphoid and myeloid lineages, respectively, use different cis-acting regulatory regions to transcribe the cytokine genes. Comparison of DNase I hypersensitivity patterns at the RAD50/IL4/IL13 locus revealed that most hypersensitive sites (HSs) are common to Th2 and mast cells, but two regions [conserved non-coding sequence (CNS) 1 and mast cell HSs] show cell type-specific differences. CNS-1, one of the most highly conserved CNS regions in the RAD50/IL13/IL4 locus, displays two strong DNase I HSs in Th2 cells but is not DNase I hypersensitive in mast cells, explaining a previous finding that deletion of CNS-1 impairs cytokine expression in Th2 cells but not in mast cells. Conversely, two constitutive HSs (mast cell HSs) in the first intron of the IL13 gene are present in mast cells but not in Th2 cells; these sites develop early during mast cell differentiation and may have a role in maintaining accessibility of the IL13 locus to high-level transcription in stimulated cells.

ATP-Binding Cassette Transporters↗
PubMed1996

Interleukin (IL)-10 inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells.

Mast cells have been implicated in a number of diseases involving chronic inflammation including asthma, rheumatoid arthritis, and inflammatory bowel diseases. They are a potent source of several cytokines, including IL-6 and TNF-alpha. Freshly isolated rat peritoneal mast cells will produce IL-6 in response to anti-IgE, LPS, PGE1, or PGE2; however, the mechanisms by which such cytokine production is regulated are poorly understood. IL-10 is recognized as an important immunoregulatory cytokine with effects on T cell development and the production of inflammatory cytokines. IL-10 has previously been described to enhance mast cell development in the context of IL-3 and IL-4. In the current study, we have examined the ability of IL-10 to modulate rat peritoneal mast cell IL-6 and TNF-alpha production in response to a variety of stimuli. We have observed that recombinant murine IL-10 can inhibit the production of both IL-6 and TNF-alpha by mast cells without altering the degree of histamine release in response to anti-IgE. Concentrations of IL-10 as low as 0.2 ng/ml were sufficient to inhibit IL-6 production by LPS- or anti-IgE-activated cells significantly. IL-10 also inhibited PGE1- and PGE2-induced IL-6 production. The relative potency of IL-10 as an inhibitor of mast cell IL-6 production was highly dependent upon the stimulus used, with a 10-fold difference in the IC50 for LPS- or anti-IgE-activated cells (0.21 ng/ml) and cells activated with a combination of LPS and PGE2 (2.29 ng/ml). This suggests that prostanoids may limit the ability of IL-10 to modulate mast cell IL-6 production in the context of inflammation. These data have important implications for the regulation of mast cell IL-6 in inflammatory diseases involving prostanoid production and the effects of treatment with cyclooxygenase inhibitors. Our results also demonstrate a dual role for IL-10 on mast cells as a growth factor and inhibitor of cytokine production.

Alprostadil↗
PubMed2005

IFN-gamma induces apoptosis in developing mast cells.

Mast cells are critical effectors of allergic disease, and are now implicated in immune responses observed in arthritis, multiple sclerosis, and heart disease. Because of their role in inflammation, understanding how mast cells develop is of clinical importance. In this study we determined the effects of IFN-gamma on mast cell survival. Using in vitro culture of bone marrow cells in IL-3 plus stem cell factor, we found that the addition of IFN-gamma induced apoptosis, as exhibited by the presence of subdiploid DNA and caspase activation. IFN-gamma-mediated apoptosis was Stat1-dependent, and was accompanied by loss of mitochondrial membrane potential. Apoptosis was reduced in cultures of bone marrow cells derived from p53- or Bax-deficient mice, as well as H2K-Bcl-2 transgenic mice. IFN-gamma hyperresponsiveness has been shown to result in inflammatory disease and death in mice lacking the regulatory protein suppressor of cytokine signaling (SOCS)-1. Bone marrow cells from SOCS-1 knockout (KO) mice failed to give rise to viable mast cells after culture in IL-3 plus stem cell factor, with profound apoptosis occurring as the cultures matured. However, bone marrow cells lacking both SOCS-1 and IFN-gamma survived normally. This in vitro defect in mast cell development was recapitulated in vivo. SOCS-1 KO mice demonstrated a 67% decrease in peritoneal mast cell numbers relative to wild-type mice, a deficiency that was reversed in SOCS-1/IFN-gamma KO mice. These data demonstrate the potent regulatory effects of IFN-gamma on mast cell survival and show that this cytokine can elicit mast cell death in vitro and in vivo.

Animals↗
PubMed1990

Replication of murine cytomegalovirus in mast cells.

Mast cells purified from the peritoneal cell population and mast cells derived in culture from bone marrow cells were examined for their sensitivity to murine cytomegalovirus (MCMV) infection in vitro. While up to 70% of mast cells expressed viral antigens, less than 12% of the cells produced infectious virus. Transmission electron microscopy demonstrated nucleocapsids in the nuclei and in association with the cisternal elements of the Golgi apparatus. Some complete virions were found within small cytoplasmic vacuoles. In contrast with previous studies of macrophages and fibroblasts, the susceptibility of mast cells to MCMV infection in vitro was not influenced by the H-2 or non-H-2 genotype of the donor.

Animals↗