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)

It is well established that human mast cell proliferation and maturation are regulated by kit ligand (stem cell factor). Little is known, however, about how these two processes are negatively regulated and thus, how mast cell number is controlled in normal and pathologic conditions. We therefore first hypothesized that SCF-dependent human mast cells would undergo programmed cell death (apoptosis) on removal of SCF as has been shown for growth factor-dependent rodent mast cells. We then examined whether SCF acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. As hypothesized, elimination of SCF from primary peripheral blood-derived human mast cell cultures resulted in a significant apoptotic process. During apoptosis, down-regulation of the two apoptosis-regulatory proteins Bcl-2 and Bcl-XL was observed. Moreover, a deregulated expression of these two proteins was found in two human mast cell lines which are SCF-independent. Thus, SCF functions as a survival factor by repressing apoptosis of human mast cells through Bcl-2 and Bcl-XL. Deregulated expression of these antiapoptotic proteins may contribute to proliferation and accumulation of mast cells in certain forms of systemic mast cell disorders.
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PMID:Human mast cell apoptosis is regulated through Bcl-2 and Bcl-XL. 1140 23

GM-CSF is known primarily as a hematopoietic growth factor, but it has also been shown to inhibit mast cell differentiation in vitro. In order elucidate the mechanisms involved, we investigated the effects of GM-CSF in vitro on the differentiation of human leukemic mast cells (HMC-1 cells) and normal cord blood-derived mast cells (CBMC) under the influence of SCF, NGF, and fibroblast supernatant (FS). Under all culture conditions, GM-CSF induced a dose- and time-dependent reduction in intracellular histamine levels, tryptase activity, and numbers of cells immunoreactive for c-Kit and FcepsilonRIalpha. This effect leveled off between 10-100 ng/ml and after 4 days of culture. There was an associated decrease in mRNA expression for c-kit, FcepsilonRIalpha and tryptase. In contrast, no significant changes in the expression of the NGF receptor TrkA were noted under the same conditions. The GM-CSF receptor was found in HMC-1 cells and CBMC at both the mRNA and protein levels, but its expression decreased during culture with FS, and even more markedly during culture with GM-CSF. GM-CSF thus selectively inhibits in vitro induction and/or upregulation of all major mast cell characteristics in HMC-1 cells and CBMC irrespective of the growth factors present, and a concomitant downregulation of GM-CSF receptors can counteract these effects. GM-CSF may therefore function as a regulatory factor in mast cell growth and differentiation under normal and pathological conditions.
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PMID:GM-CSF downmodulates c-kit, Fc(epsilon)RI(alpha) and GM-CSF receptor expression as well as histamine and tryptase levels in cultured human mast cells. 1140 70

We previously reported mast cell increases in H. pylori gastritis. To determine the mechanism, we investigated the kinetics of mast cells and mast cell growth factor (stem cell factor, SCF) in H. pylori-positive and -negative gastric mucosa. Biopsy specimens from 12 H. pylori-negative and 28 positive subjects were examined. Sections were stained for mast cells, proliferating cell nuclear antigen (PCNA), and SCF. Densities of mast cells, PCNA-positive mast cells, and SCF-positive cells were significantly greater in H. pylori-positive than -negative subjects. SCF was expressed in mast cells and fibroblasts. The density of SCF-positive fibroblasts increased in H. pylori-positive gastritis and decreased after cure of infection. SCF mRNA was detected in H. pylori-positive gastric mucosa. Fibroblasts isolated from the normal gastric mucosa expressed SCF mRNA after incubation with H. pylori water extract. SCF may be one of the factors for mast cell increase. Fibroblasts may participate in mast cell increase and inflammation in H. pylori infection.
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PMID:Stem cell factor expressed in human gastric mucosa in relation to mast cell increase in Helicobacter pylori-infected gastritis. 1185 41

We studied whether epithelial cells cultured in serum-free medium contained other cells or not, there were differences in SCF production from cultured nasal epithelial cells between groups of nonallergic and allergic patients, and among degrees of serum mite-CAP RAST classes of allergic patients, and how drugs inhibited SCF production. As a result, no other contaminating cells except mast cell existed in cultured cells. There was a significant difference in SCF production of cultured cells between nonallergic and class 1-2, 3-4, 5-6, and between class 1-2 and 3-4, 5-6 of mite CAP-RAST class. Cyclosporin, prednisolone, fluticasone, ketotifen, and clemastine inhibited SCF production from cultured epithelial cells, but cromoglicate and suplatast did not. Inhibition means the reduction of SCF from cells, not the growth of cultured nasal epithelial cells.
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PMID:[Stem cell factor production from cultured nasal epithelial cells--effect on SCF production by drugs]. 1190 54

Cross-linking of the high-affinity IgE receptor (FcepsilonRI) on mast cell activates signaling pathways that trigger degranulation and the release of multiple pro-inflammatory mediators. Mature,immature and precursor mast cells are degranulation competent. We show here that the signaling protein SWAP-70 has a function in mast cell biology. While not found in many cell types, we find that apart from B cells, mast cells also express SWAP-70. In activated B cells, SWAP-70 shuttles between cytoplasm and nucleus, but in mast cells it is confined to the cytoplasm. SWAP-70(ko/ko) (double knockout) mice have reduced numbers of mature mast cells, and these are degranulation competent. However, although immature mast cells from SWAP-70(ko/ko) mice respond normally to SCF and IL-3 and have functional granules, their FcepsilonRI-mediated degranulation is inhibited. Thus, in mast cells SWAP-70 plays a role both in establishing the initial competence to degranulate and to develop into mature mast cells.
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PMID:SWAP-70-deficient mast cells are impaired in development and IgE-mediated degranulation. 1192 May 80

The Kit receptor tyrosine kinase is critical for the growth and development of hematopoietic cells, germ cells, and the interstitial cells of Cajal. Gain-of-function mutations in codon 816 of the catalytic domain of human Kit [codon 814 of murine Kit (mKit)] are found in patients with mastocytosis, leukemia, and germ cell tumors. There are no drugs that inhibit the activity of Kit catalytic domain mutants to a greater extent than wild-type Kit. The objective of this study was to understand the biochemical mechanisms mediating mast cell transformation by this Kit mutant to identify molecular targets for pharmacological intervention. To this end, we examined signaling pathways activated in the murine mast cell line IC2 infected with either wild-type (IC2-mKit) or mutant mKit (IC2-mKit(D814Y)). In this study, we show that mKit(D814Y) is constitutively phosphorylated on tyrosine 719, and this likely results in constitutive association with activated phosphatidylinositol 3'-kinase (PI3K). In vitro growth of IC2-mKit(D814Y) cells is more sensitive to inhibition of PI3K than SCF-induced growth of IC2-mKit cells. s.c. injection of IC2-mKit(D814Y) in syngeneic mice results in mast cell tumors. To determine whether inhibition of PI3K could reduce mKit(D814Y)-mediated tumorigenicity, mice were treated with 1.5 mg/kg wortmannin three times a week. Five weeks after injection of tumor cells, a 75% reduction in tumor weight was observed when wortmannin treatments were initiated 2 days after inoculation with tumor cells. A 66% reduction occurred when treatment was initiated 2 weeks after inoculation. Treatment with wortmannin increased necrosis in the tumors, and this was associated with apoptosis. Interestingly, there was no effect on tumor vasculature. Thus, PI3K is required for survival and growth of the IC2-mKit(D814Y) mast cell line both in vitro and in vivo. These findings may provide insight into designing strategies for treatment of mastocytosis and other diseases associated with mutations in the Kit catalytic domain.
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PMID:Phosphatidylinositol 3'-kinase is required for growth of mast cells expressing the kit catalytic domain mutant. 1290 13

Mast cell tryptases may be a key mediator in mast cell-mediated inflammatory reactions, and these expressions can be regulated by microenvironmental factors of tissues, particularly stem cell factor. In the present study, we investigated whether the transcription of mouse mast cell protease-6 (mMCP-6) gene was caused by SCF-mediated c-jun. We observed that mMCP-6 mRNA was expressed by overexpression of c-jun in the immature mast cell line in which both mMCP-6 and c-kit receptor are negative. The c-jun increased synergistically the luciferase activity of mMCP-6 promoter through the direct interaction with mi transcription factor (MITF). The synergic effect of c-jun with MITF was abolished by deletion of sequence between nt -171 and -151 in the mMCP-6 promoter. Furthermore, the level of mMCP-6 mRNA in mast cells was attenuated by the introduction of dominant negative c-jun (TAM-67) and the treatment of Jun N-terminal kinase inhibitor, SP600125. These results show that c-jun might play a role in regulating the transcription of mMCP-6 gene in mast cells stimulated by SCF.
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PMID:Requirement of c-jun transcription factor on the mouse mast cell protease-6 expression in the mast cells. 1546 28

There is some evidence that, in asthma, mast cells infiltrate the airway smooth muscle layer and, as a consequence, alter the functional and structural properties of myocytes. This inflammation so-called mast-cell myositis, probably contributes to both bronchial hyperresponsiveness and airway remodelling. Previous observations have pointed out the presence of mast cells within airway smooth muscle of atopic patients and recent data obtained in asthmatic patients demonstrate that this infiltration is more important in asthmatic patients with atopy. Although the mechanism of such a mast cell attraction remains to be fully understood, experimental data demonstrate that, upon stimulation by tryptase or cytokines, smooth muscle cells can attract mast cells through the production of TGF-beta1 or SCF. Once at the site of inflammation, activated mast cells are responsible for an important extracellular deposition of inflammatory products that may facilitate the increase in smooth muscle mass. In addition, comparison of asthmatic patients with and without atopy suggests that mast cell myositis is closely related with atopy.
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PMID:Mast cell myositis: a new feature of allergic asthma? 1613 88

Our previous study showed that the number of mast cells was increased in the inflamed paws of collagen-induced arthritis in mice, and treatment with a mast cell-stabilizing compound effectively suppressed the development of collagen-induced arthritis. A recent in vitro study showed that mast cells express cysteinyl leukotriene type 1 receptor, and that a cysteinyl leukotriene type 1 receptor antagonist inhibits the production of TNF-alpha by mast cells. To further investigate the role of mast cells in vivo, we evaluated the therapeutic effects of a cysteinyl leukotriene type 1 receptor antagonist, montelukast, on the development of collagen-induced arthritis in mice. Montelukast (10 mg/kg/day) or vehicle was orally administered to mice for 12 weeks, starting 6 weeks after immunization with bovine type II collagen. Treatment with montelukast significantly reduced clinical scores and X-ray scores of collagen-induced arthritis, and decreased the number of mast cells in the inflamed paws of collagen-induced arthritic mice. Immunohistochemical analysis revealed that mast cells in the inflamed synovium were one of the major cells producing TNF-alpha and that the number of TNF-alpha positive mast cells was significantly reduced by treatment with montelukast. Furthermore, TNF-alpha and SCF mRNA levels in the paws of collagen-induced arthritic mice were markedly decreased by montelukast treatment. Montelukast may lead to a beneficial therapeutic effect by inhibiting TNF-alpha production by mast cells.
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PMID:Pathophysiological role of mast cells in collagen-induced arthritis: study with a cysteinyl leukotriene receptor antagonist, montelukast. 1694 72

There are many humoral factors that regulate the migration of mast cell progenitors from the blood into tissues and the migration of mature mast cells within tissues, leading to the rapid accumulation that occurs in diverse pathological conditions. First of all, mast cell migration is stimulated by some chemokines, such as RANTES, eotaxin, and IL-8. Moreover, many cytokines induce the migration of mast cells (i.e. SCF, TNF, IL-15). Finally, the migration of mast cells is also stimulated by many other humoral factors, including those involved in inflammatory process, such as C3a, C5a, histamine, PAF, and CRP. Because mast cells play an essential role in diverse physiological and pathological processes, it seems to be of great importance to know the mechanisms underlying the migration of immature and mature mast cells. However, current knowledge about these processes is still insufficient.
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PMID:[The regulation of mast cell migration. Part 2: mast cell chemoattractants]. 1790 17


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