Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The accumulation of mast cells in the allergic nasal epithelium is well known, yet the mechanism remains unclear. We studied whether there is a candidate for mast cell progenitors in the allergic nasal mucosa tissue removed at the time of surgery. We first confirmed that most mast cells in nasal mucosae of 10 nasal allergic patients had c-kit receptor by immunohistochemistry using the mirror sectioning technique. We then investigated whether c-kit receptor+, tryptase-, IgE- cells existed in nasal mucosae of 15 nasal allergic patients and 15 nonallergic ones using sequential triple immunohistochemistry. We observed the area in which 1,000 to 1,100 tryptase-positive cells (mast cells) existed in both the subepithelial layer and the deep layer of each nasal lamina propria. The epithelial layer above this area was also examined. Some c-kit receptor+, tryptase- cells existed in the nasal mucosae of 11 patients with nasal allergy and of 5 patients with nonallergic rhinitis. From one to four of these cells in the nasal epithelium and subepithelial layer of the 4 allergic patients were IgE-negative. In contrast, no IgE-negative cells existed in the deep layer of allergic nasal mucosae or in any nonallergic nasal mucosae. Our results suggest that mast cell progenitors, hematopoietic progenitor cells or multipotential blood cells exist in the allergic nasal mucosa, and may contribute to the increase of mast cells in the epithelium and subepithelial layer of allergic nasal mucosa.
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PMID:Existence of c-kit receptor-positive, tryptase-negative, IgE-negative cells in human allergic nasal mucosa: a candidate for mast cell progenitor. 898 Apr 62

Stem cell factor receptor (SCFR, c-kit), normally expressed on haematopoietic and mast cells, plays a regulatory role in cellular growth and differentiation. Dysregulated expression of SCFR may contribute to neoplastic transformation. We investigated expression of SCFR on malignant canine mast cells obtained directly from spontaneous canine mast cell neoplasms, in an attempt to determine whether these undifferentiated cells maintained expression of this growth-promoting cytokine receptor. Malignant mast cells (histological grade 2) from skin tumours or lymph node metastases were collected from canine patients, and SCFRs were detected by flow cytometric analysis of these cells. All of the tumours bound mouse and canine recombinant stem cell factor (SCF), indicating that the cells not only expressed SCFRs, but that the receptors possessed the functional property of ligand binding. Immunoglobulin Fc receptors for canine IgE were identified on these cells by flow cytometry, a further indication that the cells analysed were mast cells and retained some differentiated features. Immunohistochemical analysis of formalin-fixed, paraffin wax-embedded mast cell tumour biopsies confirmed expression of SCFRs by malignant cells from each tumour. The relative binding of SCF to suspensions of tumour cells, as assessed by flow cytometry, correlated with the intensity of immunolabelling for SCFR in sections of the same tumours, suggesting variability in SCFR expression between tumours. Agarose gel electrophoresis of the products of SCFR reverse transcription-polymerase chain reaction derived from each tumour had the molecular weight predicted for canine SCFR cDNA on the basis of the mouse and human counterparts. This further confirmed SCFR expression by malignant canine mast cells. Taken together, these results show that a membrane receptor capable of triggering cell growth is expressed by malignant canine mast cells, suggesting a role for this receptor in the aetiology of canine mast cell cancer. This relatively common malignancy of the dog would seem to present an opportunity for the investigation of the potential role of the SCF/SCFR pathway in the development of spontaneous malignancies of mast cells.
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PMID:Expression of stem cell factor receptor (c-kit) by the malignant mast cells from spontaneous canine mast cell tumours. 900 81

Mast cells represent a potential source of interleukin-6 (IL-6) and other cytokines that have been implicated in host defense, tissue maintenance/remodeling, immunoregulation, and many other biologic responses. In acquired immune responses to parasites or allergens, the extensive IgE-dependent activation of mast cells via Fc epsilonRI can result in the release of large quantities of biogenic amines that are stored in the cells' cytoplasmic granules as well as the production of lipid mediators and many cytokines; these products together can orchestrate an intense inflammatory response. We now report that activation of mouse mast cells via c-kit, the receptor for the pleiotropic survival/growth factor, stem cell factor (SCF), can induce the release of IL-6. Upon challenge with SCF, bone marrow-derived cultured mouse mast cells (BMCMCs) released amounts of IL-6 that were greater than 100-fold more than those produced by unstimulated cells, but that were substantially less than those produced in response to IgE and specific antigen. Moreover, BMCMCs released IL-6 upon challenge with concentrations of SCF that resulted in little or no detectable release of tumor necrosis factor-alpha, leukotriene C4, histamine, or serotonin. These findings indicate that SCF, a widely expressed protein that is critical for mast cell development and survival, can also regulate the differential release of mast cell mediators.
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PMID:Differential release of mast cell interleukin-6 via c-kit. 910 82

Mast cells are a heterogeneous family of immune cells that, when activated through their high affinity IgE receptors (Fc epsilonRI), release various granule mediators (e.g., neutral proteases and serglycin proteoglycans) and proinflammatory cytokines (e.g., IL-6 and TNF-alpha). We and others have shown that the growth and differentiation of immature, nontransformed mouse bone marrow-derived mast cells (mBMMC) can be regulated in vitro by IL-3, IL-10, and c-kit ligand. We now report that glucocorticoids inhibit the c-kit ligand- and IL-3-induced proliferation of mBMMC, the Fc epsilonRI-mediated expression of TNF-alpha, and the IL-10-mediated expression of the two chymases designated mouse mast cell protease (mMCP)-1 and mMCP-2. In contrast, glucocorticoids induce mBMMC to increase their expression of serglycin proteoglycan and carboxypeptidase A. As assessed by nuclear run-on and RNA blot analyses, dexamethasone inhibited the IL-10-mediated expression of mMCP-1 and mMCP-2, primarily by inducing rapid degradation of their transcripts. The stimulative effect on serglycin proteoglycan expression and the inhibitory effect on chymase expression were dose and time dependent and glucocorticoid specific. These findings indicate that glucocorticoids exert profound and diverse effects on the growth, cytokine expression, and granule differentiation of mouse mast cells, and that at least some of this regulation occurs through a post-transcriptional mechanism.
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PMID:Glucocorticoids inhibit the cytokine-induced proliferation of mast cells, the high affinity IgE receptor-mediated expression of TNF-alpha, and the IL-10-induced expression of chymases. 912 1

Mast cells (MC) are proinflammatory immune cells residing in various organs. Tissue-specific heterogeneity of MC has been described. The aim of this study was to establish the phenotype and functional profile of human tonsillar mast cells (ToMC) and to compare ToMC with lung-, skin-, and uterus MC. Tonsillar tissue was obtained from 23 patients suffering from hyperplastic tonsils and dispersed by enzymatic digestion. With the use of a combined toluidine blue/immunofluorescence staining technique, isolated ToMC were found to react with monoclonal antibodies (mAb) to immunoglobulin E, CD9, CD43, CD44, CD46, CD54, CD55, and CD59, as well as mAb to stem cell factor (SCF) receptor (CD117/c-kit). ToMC were not recognized by mAb to other cytokine receptors or mAb to CD3, CD11b, CD14, CDw17, the skin MC marker CD88 (C5aR) or CD89 (Fc alphaR). Activation of ToMC by recombinant human (rh) SCF or anti-IgE resulted in histamine secretion, whereas no effects were seen with rhC5a, rh granulocyte-macrophage colony-stimulating factor, or rh interleukin-1 through -10. In summary, ToMC exhibit functional and phenotypic properties similar to lung- or uterus MC. Unlike skin MC, ToMC lack C5aR and are unresponsive to rhC5a.
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PMID:Immunophenotypic and functional characterization of human tonsillar mast cells. 912 8

IgE-dependent and -independent activation of mouse bone marrow-derived mast cells (BMMC) elicited rapid and transient production of platelet-activating factor (PAF), which reached a maximal level by 2-5 min and was then degraded rapidly, returning to base-line levels by 10-20 min. Inactivation of PAF was preceded by the release of PAF acetylhydrolase (PAF-AH) activity, which reached a plateau by 3-5 min and paralleled the release of beta-hexosaminidase, a marker of mast cell exocytosis. Immunochemical and molecular biological studies revealed that the PAF-AH released from activated mast cells was identical to the plasma-type isoform. In support of the autocrine action of exocytosed PAF-AH, adding exogenous recombinant plasma-type PAF-AH markedly reduced PAF accumulation in activated BMMC. Furthermore, culture of BMMC with a combination of c-kit ligand, interleukin-1beta and interleukin-10 for > 24 h led to an increase in plasma-type PAF-AH expression, accompanied by a reduction in stimulus-initiated PAF production. Collectively, these results suggest that plasma-type PAF-AH released from activated mast cells sequesters proinflammatory PAF produced by these cells, thereby revealing an intriguing anti-inflammatory aspect of mast cells.
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PMID:Activated mast cells release extracellular type platelet-activating factor acetylhydrolase that contributes to autocrine inactivation of platelet-activating factor. 924 26

Mast cells can serve as a possible important source of cytokine production in inflamed tissue which can be regulated by stimuli different from those activating other immune system cells. To study the expression of specific genes in mast cells derived from small human colonic mucosal endoscopic biopsies, we first modified a previously reported procedure to achieve a significantly enriched mast cell fraction. Then, by using single-cell RT-PCR analysis the expression of the IgE Fc receptor (Fc epsilonRI) and c-kit mRNA was determined. It was observed that the Fc epsilonRI-positive cells also expressed c-kit. This observation provided further evidence that Fc epsilonRI-positive cells are indeed mast cells. Analysis of biopsies from 12 patients (four control and eight patients with inflammatory bowel disease (IBD)) was carried out, revealing that all of the Fc epsilonRI-positive cells expressed IL-3, while the expression of IL-4 was detected only in some of these positive cells. TNF alpha was not detected in these cells. Therefore, it would seem that most intestinal mast cells produce IL-3. Since it has been reported that IL-3 synthesis was down-regulated in steroid-treated cells, the expression pattern of IL-3 in intestinal mast cells derived from steroid-treated IBD patients was then determined. IL-3 mRNA was detected in only two out of 24 Fc epsilonRI-positive cells derived from these steroid-treated patients. These results lend strong support to the idea that the down-regulation of IL-3 in mast cells derived from steroid-treated IBD patients occurs in vivo and could be an important mechanism for immunomodulation in IBD.
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PMID:Analysis of cytokine profile in human colonic mucosal Fc epsilonRI-positive cells by single cell PCR: inhibition of IL-3 expression in steroid-treated IBD patients. 930 51

The native form of soluble c-kit ligand (KL) is a noncovalent dimer. We have isolated a soluble, disulfide-linked dimer of murine KL (KL-CD) by expressing KL in Escherichia coli and refolding the denatured protein under conditions that promote the formation of both noncovalent dimers (KL-NC) and KL-CD. KL-CD exhibits a 10- to 15-fold increase in the ability to stimulate the growth of both the human megakaryocytic cell line MO7e and murine bone marrow-derived mast cells relative to KL-NC. Colony-forming assays of murine bone marrow progenitor cells also reflected this increased potency. However, KL-CD and KL-NC are equally able to prime mast cells for enhanced IgE-dependent degranulation in vitro and activate mast cells in vivo. Improving the growth-promoting activity of KL without changing its mast cell activation potential suggests that KL-CD or a related molecule could be administered in the clinic at doses that stimulate hematopoietic recovery while avoiding significant mast cell activation.
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PMID:Increased growth promoting but not mast cell degranulation potential of a covalent dimer of c-Kit ligand. 935 54

Murine studies have demonstrated that, as with other nematodes, infection with the intestinal nematode Trichinella spiralis is associated with a pronounced intestinal mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)-4 and IL-5 are clearly important in the generation of IgE responses and eosinophilia, respectively, but the control of mucosal mastocytosis in vivo is not as well defined. Mucosal mast cells appear to be particularly important with regard to T. spiralis infections as there is good evidence to suggest their involvement in expulsion of the parasite from the host. In this study we examined the effect of the overproduction of the Th2 cytokine IL-9 on infection with this nematode. We demonstrate that naive IL-9-transgenic mice have an intense intestinal mastocytosis and high serum levels of mouse mast cell protease-1. Moreover, upon infection high titers of parasite-specific IgG1 were observed with a heightened mast cell response, which was associated with the rapid expulsion of T. spiralis from the gut. Furthermore, as depression of this mast cell response, using anti-c-kit antibodies, resulted in the inability of these mice to expel the parasite, this study clearly demonstrates an activity of IL-9 on mucosal mastocytosis and the host protective immune response in vivo.
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PMID:Interleukin-9 is involved in host protective immunity to intestinal nematode infection. 936 7

Emerging evidence has suggested the pivotal role of mast cells in a host defense against bacterial infection. In this paper, we report that bacterial lipopolysaccharide (LPS) is a potent enhancer of the cytokine- and IgE-dependent delayed responses of IL-3-dependent mouse bone marrow-derived cultured mast cells (BMMC). LPS, although showing minimal effects, significantly augmented the c-kit ligand (KL)- or IgE-dependent expression of cyclooxygenase (COX)-2 and the attendant delayed PGD2 generation, with IL-10 and IL-4 acting as potentiating and inhibitory cytokines, respectively. The COX-2-inducing activity of LPS was mimicked by exogenous IL-1 beta. Assessment of endogenous cytokine induction revealed that IL-1 beta expression was stimulated by either LPS or exogenous IL-1 beta. IL-6 expression occurred in parallel with COX-2 expression. IL-10 expression, which lagged behind COX-2 expression, depended on exogenous IL-10, but not on LPS and IL-1 beta. Thus, LPS and IL-1 beta exhibited similar biological activities in terms of COX-2 and endogenous cytokine expression. However, adding an antibody against the type I IL-1 receptor to BMMC, which abrogated the effects of IL-1 beta, failed to neutralize the effects of LPS. These results suggest that LPS activates BMMC through the signal transduction pathway shared with exogenous IL-1 beta, rather than exerting its action indirectly via the production of endogenous IL-1 beta.
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PMID:Regulation of cyclooxygenase-2 and endogenous cytokine expression by bacterial lipopolysaccharide that acts in synergy with c-kit ligand and Fc epsilon receptor I crosslinking in cultured mast cells. 963 92


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