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)

Mastocytosis is a disease characterized by an abnormal proliferation of tissue mast cells. The events primarily responsible for mast cell proliferation in mastocytosis are largely unknown, but a derangement of the network involving c-kit receptor and its natural ligand (stem cell factor, which promotes mast cell growth and differentiation in man) is likely to have a primary role in this disease. Mastocytosis comprises a wide spectrum of clinical conditions determined by the degree of mast cell proliferation, the organ systems involved, the age at onset and the association with hematologic diseases. Mastocytosis can occur in a pediatric or an adult form. In both groups of patients, the disease may be limited to the skin (cutaneous mastocytosis) or be systemic, involving predominantly the bone marrow and the gastrointestinal tract. The symptoms in patients with mastocytosis are generally related to the increased release of mast-cell-derived mediators, such as histamine, prostaglandin D2, peptide leukotrienes, platelet-activating factor, heparin and proteolytic enzymes. The measurement of these chemical mediators (histamine, tryptase and prostaglandin D2 and their metabolites) in body fluids is useful for the diagnosis and the laboratory evaluation of patients with systemic mastocytosis. As little is known about the pathogenesis of the different forms of mastocytosis, the treatment of the majority of these patients is largely symptomatic.
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PMID:Clinical advances in mastocytosis. 878 45

Stem cell factor (SCF) is a growth factor with multiple activities which acts on numerous cell types including primordial germ cells, haemopoietic stem cells, melanocytes and mast cells. SCF is critical for the development of the mast cell hyperplasia associated with infection with the intestinal parasites Nippostrongylus brasiliensis and Trichinella spiralis. In the present study we have assessed the role of SCF in the mast cell and eosinophil responses to Schistosoma mansoni in the rat by blocking its effects in vivo with polyclonal antibody to SCF. Rats treated with sheep anti-SCF antibody on days 21, 24, 27 and 30 of infection with S. mansoni showed a rapid decrease in serum concentrations of the mucosal mast cell-associated protease rat mast cell protease II (RMCP II) by day 24, compared with normal sheep IgG-treated controls. Similarly, the number of mucosal mast cells and RMCP II levels in both small intestine and liver were also significantly reduced by day 32 of infection. In contrast with the depeletion of mast cells and mast cell proteases, eosinophil numbers in liver or intestine did not change significantly after anti-SCF treatment compared with controls. These results confirm that mast cell survival and hyperplasia are dependent on the presence of SCF whilst demonstrating that the eosinophil recruitment to liver and intestine associated with S. mansoni infection is SCF-independent.
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PMID:Stem cell factor dependent hyperplasia of mucosal-type mast cells but not eosinophils in Schistosoma mansoni-infected rats. 881 6

Neuropeptides such as substance P are released from nerve terminals following the stimulation of sensory fibers, and are thought to participate in neurogenic inflammation in the skin; it is often speculated that mast cell activation is an intermediate step in this process. In the present study we addressed this hypothesis using freshly obtained skin explants derived from human neonatal foreskins or adult skin resections. The results demonstrate that when substance P is released from human skin by incubation in the presence of capsaicin (10(-5)M), no histamine is released from human isolated skin fragments. In each experiment human recombinant stem cell factor and/or exogenously applied substance P effectively evoked histamine release from the explants, attesting to the viability of the mast cells in the preparation. The concentrations of exogenously applied substance P required to elicit histamine release, however, were large (> 10 microM). These results indicate that substance P released from cutaneous sensory nerve fibers does not reach sufficient concentrations in the skin to degranulate mast cells. These data support the hypothesis that the vascular effects of neurogenic inflammation occur independently of mast cell activation.
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PMID:Exogenous but not endogenous substance P releases histamine from isolated human skin fragments. 883 63

Cell priming and stimulation of different cytokines (which include chemokines and growth factors) are typical features of human basophils. Recently, it has been shown that the macrophage chemotactic protein-1 (MCP-1), RANTES and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are potent direct secretagogues for human basophils and that interleukin-3 (IL-3), IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are priming factors for subsequent potentiation of mediator release from basophils induced by different stimuli. This observation may be clinically important for the activation and recruitment of inflammatory cells in different immune responses of the skin (e.g. late-phase reactions). The aim of the present study was to investigate whether cytokines and chemokines are also capable of priming or stimulating isolated human skin mast cells (SMC). SMC were either stimulated directly with the cytokines alone or preincubated with these factors for 10 min before being activated with suboptimal concentrations of anti-IgE, A23187 or substance P. IL-3, IL-5, GM-CSF, platelet factor-4 (PF-4), IL-8, MCP-1 and MIP-1 alpha (each at concentrations of 1 ng/ml to 1 microgram/ml, log steps) did not significantly modulate histamine release from SMC induced by the three different secretagogues. RANTES exhibited a weak but significant potentiating effect on IgE-mediated activation. Stem cell factor (SCF) as a positive control was able to prime mast cell histamine release strongly. In addition, PF-4, MCP-1, RANTES and MIP-1 alpha were incapable of inducing direct histamine release from SMC. In experiments with isolated human peripheral basophils, however, we observed potent Fc epsilon RI-mediated priming effects evoked through IL-3, IL-5 and GM-CSF. We conclude that SMC derived from healthy donors are not targets of (immuno)modulatory factors that prime or stimulate basophils.
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PMID:Effects of basophil-priming and stimulating cytokines on histamine release from isolated human skin mast cells. 884 26

Stem cell factor (SCF) is potent activator of degranulation of rat peritoneal mast cells in vitro and may promote mast cell activation under certain circumstances in vivo. In this study we report that the anti-inflammatory glucocorticoid dexamethasone (DEX) and the immunosuppressive cyclosporin A (CsA) are both effective inhibitors of SCF-induced degranulation of rat peritoneal mast cells in vitro, measured as release of serotonin (5-HT). Of the two drugs, DEX was the more potent with near maximal inhibition reached at 10(-8) M, whereas a graded inhibition was seen with CsA in the range 10(-8)-10(-6) M. DEX was equally effective in inhibiting the release of 5-HT induced by either SCF or anti-IgE, but was less effective in inhibiting release induced by compound 48/80 or calcium ionophore A23187. CsA produced a similar degree of inhibition of degranulation induced by SCF, anti-IgE or ionophore, but was without effect on the response to compound 48/80. Neither DEX nor CsA had any significant effect on mast cell surface expression of the SCF receptor or IgE antibody. We conclude that both DEX and CsA inhibit components of the secretion-coupling pathways that are triggered following either SCF receptor engagement or cross-linking of IgE, but that these drug differentially influence mast cell secretion induced by compound 48/80 or the calcium ionophore A23187.
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PMID:Dexamethasone or cyclosporin A inhibits stem cell factor-dependent secretory responses of rat peritoneal mast cells in vitro. 888 Feb 26

It has been reported that the administration of interferon alpha-2b is of potential benefit in the treatment of mastocytosis based on a single patient study (NEJM, Feb 27, 1992, 326(9):619-623). Following this report, we administered interferon alpha-2b at a dose of 4 to 5 million units per square meter of body surface area for at least 12 months to one patient with mastocytosis with an associated hematologic disorder (patient 1), one patient with aggressive systemic mastocytosis (patient 2), and one patient with indolent mastocytosis (patient 3). Patients were monitored with the following clinical and laboratory parameters: serial bone marrow biopsies and aspirates, patient log of histamine release attacks, medication dependency, plasma tryptase levels, serum lactate dehydrogenase (LDH) levels, white blood cell counts and differentials, extent of urticaria pigmentosa lesions, bony involvement, and extent of gastrointestinal involvement and hepatomegaly. We also examined the ability of interferon alpha-2b to inhibit recombinant human stem cell factor (rhSCF)-dependent mast cell proliferation from CD34+ bone marrow-derived cells. All patients demonstrated continued progression of disease in one or more clinical criteria at one year of therapy. Similarly, interferon alpha-2b did not inhibit the culture of mast cells from CD34+ bone marrow-derived cells in the presence of SCF. Thus, in our study of three patients with systemic mastocytosis, treatment with interferon alpha-2b was found to be ineffective in controlling progression of disease.
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PMID:Treatment of three patients with systemic mastocytosis with interferon alpha-2b. 888 64

Nerve growth factor (NGF) promotes mast cell survival in vitro (Horigome, K., Bullock, E. D., and Johnson, E. M., Jr. (1994) J. Biol. Chem. 269, 2695-2702). NGF survival promotion is cell density-dependent, and conditioned medium experiments have shown that NGF increases the production of an autocrine mast cell survival activity. Cytokines are potential candidates for autocrine survival factors. In rat peritoneal mast cells (RPMC), NGF caused an increase in the messenger RNAs for interleukin (IL)-3, IL-4, IL-10, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor. This induction was NGF dose-dependent, was blocked by NGF-neutralizing antibodies, and was not observed in the non-mast peritoneal cell population. The immunosuppressive agent, cyclosporin A, blocked both cytokine induction and NGF-activated survival promotion but not survival promotion activated by IL-3 or stem cell factor, suggesting that NGF enhanced RPMC survival by increasing cytokine production. We also examine the effects of NGF on the expression levels of some members of the bcl-2 family and the interleukin-1beta-converting enzyme-like cysteine protease families. NGF markedly increased bcl-2 expression but had little or no effect on the other genes studied. The induction of bcl-2 mRNA by NGF was not blocked by cyclosporin A. These data suggest that induced cytokine gene expression but not increased expression of bcl-2 mediates NGF-survival promotion in RPMC.
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PMID:Nerve growth factor induces the expression of certain cytokine genes and bcl-2 in mast cells. Potential role in survival promotion. 891 Mar 34

Recent data suggest that local overexpression of the tissue-hormone c-kit ligand (stem cell factor [SCF]) is associated with accumulation of mast cells (MCs) and a decrease in expression of c-kit in the accumulated MCs [28]. In the present study, the effects of recombinant human (rh) SCF on expression of c-kit mRNA and c-kit protein in isolated human MCs and a human mast cell line, HMC-1, were analyzed. Incubation of isolated lung MC with rhSCF (100 ng/mL) for 120 minutes resulted in decreased expression of c-kit mRNA (optical density [OD], control: 100% vs. rhSCF: 37%). Almost identical results were obtained with HMC-1 cells (OD, control: 100% vs. rhSCF: 40 to 45%). As assessed by flow cytometry and monoclonal antibodies (mAbs) to c-kit, the SCF-induced decrease of c-kit mRNA in HMC-1 was associated with a substantial decrease in surface expression of c-kit (MFI, control: 100 +/- 21%, vs. MFI in cells incubated with rhSCF [100 ng/mL at 37 degrees C for 12 hours]: 8 +/- 2%, vs. MFI in cells incubated with rhSCF, 100 ng/mL, at 4 degrees C: 34 +/- 3%). The effects of rhSCF on c-kit expression in HMC-1 cells were dose- and time-dependent with maximum effects observed with 10-100 ng/mL of rhSCF after 4 to 12 hours. The SCF-dependent loss of c-kit was also accompanied by a decreased chemotactic response to rhSCF (control: 100%; rhSCF: 71 +/- 2%). This study shows that exposure of human lung MC and HMC-1 cells to recombinant SCF results in downregulation of c-kit mRNA and surface c-kit expression. These data may explain the partial loss of c-kit on MCs in areas of SCF overexpression.
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PMID:Stem cell factor-induced downregulation of c-kit in human lung mast cells and HMC-1 mast cells. 891 83

We followed the response of muscle following mild intentional injury to determine a temporal sequence of cellular events involved in muscle repair. We found that intramuscular saline injection induced mild damage to muscle which resulted in the gradual recruitment of mast cells. Around the needle track, mast cells appear around 8 h post-injection. Mast cell accumulation were most dramatic immediately neighboring the posterior tibial vessels supplying the injured muscle. Dystrophin-deficient mdx muscle showed mast cell accumulations 3-fold higher than normal muscle, and this number did not change after saline injection. Additionally, we show that stem cell factor (SCF), a known mast cell chemoattractant, is expressed in both normal and mdx muscle at high levels. This steady-state level did not appear to be influenced by injury or dystrophin status. The implications of these findings are discussed as they relate to the repair of injured muscle and to their possible significance in the pathophysiology of Duchenne muscular dystrophy.
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PMID:Recruitment of mast cells to muscle after mild damage. 892 90

Using mouse peritoneal mast cells, we investigated the effects of 1 alpha,25-dihydroxyvitamin D3 (calcitriol) on mast cell proliferation and histamine release. Calcitriol did not affect IL-3/IL-4-dependent mast cell proliferation, but it selectively inhibited stem cell factor-dependent mast cell proliferation and colony formation. Immunohistochemical and immunoblot analyses revealed that calcitriol treatment reduced expression of purified peritoneal mast cell c-kit protein. Using a mast cell line, MC/9, both c-kit protein and c-kit mRNA transcript were seen to be reduced following calcitriol treatment. Calcitriol also reduced histamine release induced by calcium ionophore A23187. In contrast, anti-IgE antibody-dependent histamine release was not affected by calcitriol. Our results indicate that calcitriol inhibits mast cell proliferation and A23187-induced histamine release that might be associated with a decreased expression of c-kit receptor.
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PMID:Inhibitory effect of 1 alpha,25-dihydroxyvitamin D3 on mast cell proliferation and A23187-induced histamine release, also accompanied by a decreased c-kit receptor. 893 75


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