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)

Mast cells are the principal effector cells in IgE-dependent hypersensitivity reactions. Despite reports that rodent mast cells proliferate in the presence of nerve growth factor (NGF), human mast cells reportedly do not respond to this factor. To determine if human mast cells express the NGF receptors, TrkA tyrosine receptor and the low affinity NGF receptor (LNGFR), we first analyzed the mRNA expression by RT-PCR of TrkA and LNGFR in a human mast cell line (HMC-1) and in human mast cells cultured in the presence of stem cell factor. Both HMC-1 and cultured human mast cells were found to express TrkA but not LNGFR. TrkA protein was demonstrated by Western blot analysis of HMC-1 lysates. Using flow cytometric analysis and mast cell tryptase as a mast cell marker, both HMC-1 cells and cultured human mast cells were shown to coexpress tryptase and TrkA. Treatment of mast cells with NGF resulted in phosphorylation of TrkA on tyrosine residues as detected by immunoblotting with an antiphosphotyrosine antibody. Furthermore, NGF induced the immediate early gene c-fos in HMC-1 cells. HMC-1 cells and cultured human mast cells were also found to express NGF mRNA, and conditioned medium from HMC-1 cells stimulated neurite outgrowth from chicken embryonic sensory ganglia in culture. This effect was blocked by anti-NGF. Thus, mast cells express functional TrkA and synthesize NGF, suggesting a mechanism by which NGF may act as an autocrine factor for human mast cells, and by which mast cells and nerves may interact.
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PMID:Human mast cells express functional TrkA and are a source of nerve growth factor. 934 72

Maternal separation in neonatal rodents causes a wide range of behavioural and metabolic alterations, affecting the physiological response of the neuro-immune-endocrine system. For example, interference with the normal mother-infant interactions leads to an increased susceptibility to experimentally-induced allergic encephalomyelitis (EAE) in adult life. Since it has been reported that mast cells (MCs) participate in the pathophysiology of the autoimmune inflammatory disease multiple sclerosis (MS) and also EAE and that brain nerve growth factor (NGF) levels are altered in EAE, studied whether maternal separation and gentle manipulation (gentling) of neonatal Lewis rats perturb NGF levels or MC distribution in the brain. EAE-induction susceptibility in adult life was also evaluated and NGF levels and mast cell distribution within the hippocampus and thalamus were measured at 0, 10, 20 and 60 postnatal days. Our results show an exacerbation of clinical signs in rats separated from mothers where EAE was induced, a general decrease in NGF protein levels and MC number in the hippocampus during the first developmental period and significant increase in the number of MC in the hippocampus and the thalamus at young-adulthood (60 days of age). These results indicate that disruption of the maternal bond during early infancy may produce long-lasting alterations in the brain cellular and molecular environment, leading to increased susceptibility to EAE in adult life.
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PMID:Neonatal handling in EAE-susceptible rats alters NGF levels and mast cell distribution in the brain. 966 17

Stem cell factor (SCF) stimulates mast cell adhesion and, because SCF is produced normally in tissues, it may be a major factor responsible for the adhesion of mast cells to connective tissue matrix. We found that the morphology of rat peritoneal mast cells (RPMC) altered after the addition of recombinant murine SCF (rmSCF) in vitro. The ability of rmSCF to enhance morphological alteration was dose dependent and completely abolished by anti-c-kit ACK2 monoclonal antibody. Exposure of RPMC to transforming growth factor-beta 1, wortmannin, genistein, herbimycin A, staurosporine, indomethacin and cytochalasin D before the addition of rmSCF antagonized rmSCF-induced morphological alteration. However, nordihydroguiaretic acid had no effect. Many RPMC appeared to respond also to nerve growth factor (NGF) but the total number of cells with altered morphology was much greater when the culture was stimulated by rmSCF than by NGF. We suggest that morphological alterations of mast cells by rmSCF is an important step for the participation in adhesion to tissue under resident physiological conditions.
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PMID:Morphological alterations in rat peritoneal mast cells by stem cell factor. 974 47

In addition to its neuronal effects, nerve growth factor (NGF) is known to act on inflammatory and immune cells. The aim of the present study was to investigate the effect of colchicine on NGF-induced leukocyte accumulation and thermal hyperalgesia. Initial experiments showed that intradermal injection of recombinant human (rh) NGF (0.8 and 4 microg) caused a longlasting increase in tissue myeloperoxidase (MPO) indicating leukotactic activity of NGF. Colchicine (0.3 and 1 mg/kg) attenuated the NGF (0.8 and 4 microg)-induced increase in tissue myeloperoxidase (MPO) as determined 6 h after NGF application. Intraplantar injection of NGF into the rat hindpaw caused a decrease in thermal nociceptive threshold, which, at 4 microg NGF, was accompanied by moderate (about 35% increase in paw volume) edema. The thermal hyperalgesia was evident 20 min after injection and lasted less than 4 h. Colchicine (0.3 and 1 mg/kg) had no significant effect on NGF-induced edema, but reduced NGF-induced thermal hyperalgesia. Colchicine (1 mg/kg) did not significantly reduce thermal hyperalgesia produced by intraplantar bradykinin, prostaglandin E1, or 5-hydroxytryptamine. Treatment of rats with a dose of indometacin (2 mg/kg) that was sufficient to block cyclooxygenase had no significant effect on NGF-induced thermal hyperalgesia or edema. In vitro, colchicine (0.4-12 microg/ml) did not significantly influence NGF (10 ng/ml)-induced histamine release from rat peritoneal cells, suggesting that a mast cell stabilizing effect of colchicine did not contribute to inhibition of NGF-induced thermal hyperalgesia. The results show that NGF causes localized indometacin-resistant thermal hyperalgesia that can be blocked by the microtubule disrupting agent colchicine. These results raise the possibility that a mechanism by which NGF produces peripheral sensitization is related to its leukotactic effect.
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PMID:Effect of colchicine on nerve growth factor-induced leukocyte accumulation and thermal hyperalgesia in the rat. 975 13

We have previously shown that fibroblast and keratinocyte supernatants up-regulate expression of mast cell characteristics in the human immature mast cell line HMC-1. This effect could not be induced in HMC-1 cells by the well-known mast cell growth factor stem cell factor (SCF), probably due to mutations of the SCF receptor c-Kit in these cells. Here we report the effects of several known fibroblast- and keratinocyte-derived growth factors, namely nerve growth factor (NGF), basic fibroblast growth factor, platelet-derived growth factor and transforming growth factor-beta, on mast cell differentiation, using HMC-1 cells as a model. NGF, at 0.1-50 ng/ml concentrations, caused a marked, dose-dependent up-regulation of tryptase, Fc epsilon RI and histamine within 10 days of culture, associated with an enhanced expression of mRNA for Fc epsilon RI and mast cell tryptase. On restriction analysis, only mast cell beta-tryptase, but not alpha-tryptase, could be demonstrated. Furthermore, the high-affinity NGF receptor (TrkA) was found at both the transcriptional and protein levels, while expression of the low-affinity NGF receptor was detectable at the mRNA level only. None of the other growth factors caused a significant alteration of the mast cell markers studied when added to HMC-1 cells at concentrations known to be biologically active in other culture systems. Immature human mast cells are thus induced to assume a more mature phenotype in vitro in response to NGF, most probably via stimulation of the high-affinity NGF receptor expressed on these cells. Besides SCF, NGF should therefore be considered as an additional mast cell growth factor that contributes to human mast cell maturation at tissue sites.
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PMID:Effects of nerve growth factor (NGF) and other fibroblast-derived growth factors on immature human mast cells (HMC-1). 977 35

Mast cells derive from a distinct bone marrow precursor and mature in tissues under the influence of stem cell factor, nerve growth factor (NGF) and certain interleukins. Intracranial mast cells first appear in the meninges and are located perivascularly close to neurons. They can be activated by antidromic stimulation of the trigeminal nerve, as well as by acute immobilization stress. Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly potent in stimulating mast cell release of vasoactive, inflammatory and nociceptive molecules. These findings have suggested that mast cells may be involved in neuroinflammatory conditions, such as migraines. In this study, dura mast cells were shown to have characteristics of connective tissue mast cells (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP-I). Mast cells were localized close to SP-positive neurons immunocytochemically and mast cell-neuron contacts were also documented using scanning electron microscopy. Dura stimulated by SP and carbachol in situ released histamine. Preincubation of dura with estradiol slightly augmented histamine release by SP, an effect possibly mediated through estrogen receptors identified on dura mast cells. Acute stress by immobilization led to dura mast cell degranulation which was prevented by pretreatment with a neutralizing antibody to CRH or a CRH receptor antagonist. The present results further clarify the biology of intracranial mast cells and support their involvement in the pathophysiology of migraines which are precipitated or worsened by stress.
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PMID:Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. 1059 82

Despite being a well-characterized neurotrophic factor, nerve growth factor (NGF) influences survival, differentiation, and functions of mast cells. We investigated whether NGF was able to induce directional migration of rat peritoneal mast cells (PMCs). NGF clearly induced chemotactic movement of PMCs in a dose-dependent manner with the drastic morphological change and distribution of F-actin, which was completely blocked by pretreatment with Clostridium botulinum C(2) toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors specific for MAPK kinase and PI3K suppressed cell migration and these signals. In the coculture system with PMCs and fibroblasts, which produce biologically active NGF, directional migration of PMCs to fibroblasts was observed, and the addition of anti-NGF polyclonal antibodies significantly suppressed the migration of PMCs. These findings suggested that NGF initiated chemotactic movement of PMCs through both MAPK and PI3K signaling pathways following TrkA activation. Thus, locally produced NGF may play an important role in mast cell accumulation in allergic and nonallergic inflammatory conditions. (Blood. 2000;95:2052-2058)
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PMID:Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. 1070 74

To examine the possible roles of mast cells in the pathogenesis of subcapsular cell hyperplasia (SCH) in the adrenal glands of mice, we investigated the expression of certain cytokines, including stem cell factor (SCF), tumor necrosis factor-alpha (TNF-alpha), nerve growth factor (NGF), and basic fibroblast growth factor (bFGF), and mast cell-specific proteases, such as mouse mast cell protease (mMCP)-2 and mMCP-7. The mRNAs of c-kit (SCF receptor), bFGF, TNF-alpha, mMCP-2, and mMCP-7 were expressed in both the adrenal glands and the mouse bone marrow-derived mast cells (mBMMCs). Immunoreactivities for cytokines (SCF, NGF, TNF-alpha) and proteases (mMCP-2, mMCP-7) were exclusively located in the mast cells in SCH lesions. The immature mBMMCs did not express the mRNAs of SCF and NGF, whereas the mast cells in the SCH lesions showed the expression of SCF and NGF. These findings suggest that SCH may provide a favorable microenvironment for functional maturation of mast cells to produce SCF and NGF, and the mast cells in SCH lesions synthesize SCF and NGF and may, in part, use them in autocrine fashion for their survival and differentiation. Therefore, mast cells may contribute to SCH pathogenesis by producing a range of multifunctional cytokines and proteases.
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PMID:Expression of cytokines and proteases in mast cells in the lesion of subcapsular cell hyperplasia in mouse adrenal glands. 1080 47

Mast cell hyperplasia is observed in various inflammatory skin diseases. Although the pathogenesis of these conditions remains largely uninvestigated, it has been speculated that lesional mediators provide a favorable microenvironment for mast cell growth. We investigated the effect of an inflammatory cytokine, IL-1 alpha, on mast cell growth in a mast cell/fibroblast coculture system. When mouse bone marrow-derived cultured mast cells (BMMC) were cultured on a NIH/3T3 fibroblast monolayer, IL-1 alpha stimulated mast cell proliferation. However, IL-1 alpha did not stimulate 3H-thymidine incorporation in BMMC in the absence of fibroblasts. Separation of BMMC from fibroblasts by a permeable micropore membrane reduced the effect of IL-1 alpha. When BMMC were prepared from W/Wv mice, which lack a functional c-kit, or when NIH/3T3 fibroblasts were substituted with Sl/Sld-derived fibroblasts, which lack membrane-bound stem cell factor (SCF), a lower, but significant, effect of IL-1 alpha was observed. Flow cytometric analysis revealed no enhancement of SCF expression on fibroblasts following stimulation with IL-1 alpha. Neutralizing antibodies against IL-3, IL-4, IL-10, and nerve growth factor (NGF) showed no inhibition. On the other hand, indomethacin inhibited the effect of IL-1 alpha, and prostaglandin E2 induced mast cell growth in the co-cultures. These results indicate that IL-1 alpha stimulates mast cell growth by a fibroblast-dependent mechanism, in which SCF/c-kit interaction may participate in a major way. The mast cell growth activity induced by this cytokine can, at least in part, be attributed to prostaglandins. Inflammatory cytokines may thus contribute to mast cell hyperplasia in skin diseases.
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PMID:Interleukin-1 alpha enhances mast cell growth by a fibroblast-dependent mechanism. 1086 12

In the adult rat brain mast cells reside selectively in the thalamus. We investigated thalamic mast cells stained by acidic toluidine blue or pinacyanol, and with histamine immunocytochemistry, focusing on their state of activity revealed by degranulation. Mast cells exhibited perivascular prevalence and high quantitative variability, between cases and in different sections, with no asymmetry or topographical selectivity in thalamic nuclei. Pinacyanol, alone or with erythrosine, stained mast cells with higher sensitivity than toluidine blue. However, toluidine blue was highly predictive of pinacyanol staining and provided the best resolution of mast cell cytoplasmic features. Histamine immunocytochemistry labeled 61% of pinacyanol-stained mast cells. Intensely toluidine blue-stained granulated cells, as well as cells exhibiting different degrees of degranulation that paralleled lighter staining, were observed. The response of thalamic mast cells to intracerebroventricular administration of nerve growth factor (NGF) and control cytochrome-c injections was evaluated after 2, 24, and 72 hours. No obvious changes in mast cell number or distribution were found after treatment, but massive degranulation was frequently observed after NGF administration. Significant decrease of staining intensity of mast cells, supporting enhanced degranulation, was documented in NGF-treated animals by quantitative image analysis. Ultrastructural features of mast cell degranulation, with granule coalescence and matrix dissolution, were detected in untreated and NGF-treated cases. The findings point out that mast cells are active in the thalamus in basal conditions and that NGF has the potential to elicit long-lasting degranulation of thalamic mast cells in vivo, exerting a direct effect and/or priming these cells to react to endogenous stimuli.
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PMID:Degranulation, density, and distribution of mast cells in the rat thalamus: a light and electron microscopic study in basal conditions and after intracerebroventricular administration of nerve growth factor. 1093 87


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