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 may participate in tumor angiogenesis through the release of angiogenic cytokines from their secretory granules. To gain additional insight into the role of mast cells in bone marrow angiogenesis, we performed a semiquantitative measurement of bone marrow microvessel density in 52 consecutive adult patients with systemic mast cell disease (SMCD). The results were examined for potential correlations with mast cell expression of angiogenic cytokines and with other histologic features of the bone marrow. Standard immunohistochemical methods were used to visualize bone marrow microvessels (CD34 staining) and mast cell expression of transforming growth factor-beta, basic fibroblast growth factor, and their respective receptors. An increase in microvessel density was demonstrated in 32 of the 52 patients (62%) with SMCD, and the degree of bone marrow angiogenesis did not correlate with either the mast cell expression pattern of the study cytokines or the presence (23 patients) or absence (29 patients) of an associated hematologic disorder. In the 29 patients without an associated hematologic disorder, microvessel density was correlated significantly with the presence of an abnormal pattern of hematopoiesis but not with the degree of bone marrow involvement by mast cells. Furthermore, areas occupied by mast cell lesions were often devoid of neovascularization. We conclude that bone marrow angiogenesis characterizes a percentage of patients with SMCD and that the pathogenesis may not necessarily be linked to the mast cells themselves.
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PMID:Bone marrow angiogenesis in systemic mast cell disease. 1184 10

Mastocytosis is a rare stem cell disorder characterized by abnormal growth and accumulation of mast cells in one or more organ systems. Clinical heterogeneity is a hallmark of mastocytosis. Recent observations of activating mutations in c-kit may help to understand the abnormal growth of mast cells in mastocytosis. However, this mutation alone does not explain the entire clinical heterogeneity of the disease. Reticulin fibrosis is also commonly associated with systemic mastocytosis. Mast cells are known to be the source of fibrogenic cytokines, including platelet-derived growth factor, transforming growth factor-beta (TGF beta) and basic fibroblast growth factor (bFGF). Immunohistochemical studies show a close correlation between the mast cell expression of bFGF and the reticulin fibrosis of mastocytosis lesions. The study of cytokine receptor expression also demonstrates that the TGF beta receptor I (RI)-negative cases of mastocytosis are prognostically less favorable than the TGF beta RI-positive cases. This finding may be related to the fact that the TGF beta R complex functions as a tumor suppressor gene in neoplastic cells.
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PMID:Mastocytosis and fibrosis: role of cytokines. 1191 21

Activins, members of the transforming growth factor-beta (TGF-beta) superfamily, are potent growth and differentiation factors. Our previous studies revealed that activin A, a homodimer of inhibin/activin beta(A), was induced in mast cells and peritoneal macrophages in response to their activation. In the present study, we examined the roles of activin A in murine bone marrow-derived, cultured mast cell progenitors (BMCMCs), which expressed gene transcripts for molecules involved in activin signaling, suggesting that BMCMCs could be target cells of activin A. Treatment of activin A inhibited 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide uptake into BMCMCs in a dose-dependent manner. The IC(50) concentration was 2.1 nM, which was less potent than 185 pM TGF-beta(1). Activin A treatment caused morphological changes toward the differentiated cells at 2 nM and up-regulated mRNA of mouse mast cell protease-1 (mMCP-1), a marker enzyme of mature mucosal mast cells, at 1 nM. Activin A also showed activity in inducing migration of BMCMCs; the optimal concentration for maximal migration was 10 pM, which was much lower than the concentrations to inhibit cell growth and to activate the mMCP-1 gene. Taking the present results together with our previous results, it is suggested that activin A secreted from activated immune cells recruits mast cell progenitors to sites of inflammation and that with increasing activin A concentration, the progenitors differentiate into mature mast cells. Thus, activin A may positively regulate the functions of mast cells as effector cells of the immune system.
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PMID:Role of activin A in murine mast cells: modulation of cell growth, differentiation, and migration. 1277 12

Chymase is contained in the secretory granules of mast cells. In addition to the synthesis of angiotensin II, chymase is involved in transforming growth factor-beta activation and cleaves Type I procollagen to produce collagen. NK301 and BCEAB are orally-active inhibitors of chymase. NK301 was tested in a dog model of vascular intimal hyperplasia after balloon injury and shown to reduce the increased chymase activity in the injured arteries and prevent intimal thickening. In a hamster model of cardiac fibrosis associated with cardiomyopathy, BCEAB reduced the increased cardiac chymase activity in cardiomyopathy and reduced fibrosis. Chymase inhibitors may be an important development for the treatment of cardiovascular injury associated with mast cell degranulation.
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PMID:Will chymase inhibitors be the next major development for the treatment of cardiovascular disorders? 1288 28

Large animal models have provided much of the descriptive data regarding the cellular and molecular events in myocardial infarction and repair. The availability of genetically altered mice may provide a valuable tool for specific cellular and molecular dissection of these processes. In this report we compare closed chest models of canine and mouse infarction/reperfusion qualitatively and quantitatively for temporal, cellular, and spatial differences. Much like the canine model, reperfused mouse hearts are associated with marked induction of endothelial adhesion molecules, cytokines, and chemokines. Reperfused mouse infarcts show accelerated replacement of cardiomyocytes by granulation tissue leading to a thin mature scar at 14 days, when the canine infarction is still cellular and evolving. Infarcted mouse hearts demonstrate a robust but transient postreperfusion inflammatory reaction, associated with a rapid up-regulation of interleukin-10 and transforming growth factor-beta. Unlike canine infarcts, infarcted mouse hearts show only transient macrophage infiltration and no significant mast cell accumulation. In correlation, the growth factor for macrophages, M-CSF, shows modest and transient up-regulation in the early days of reperfusion; and the obligate growth factor for mast cells, stem cell factor, SCF, is not induced. In summary, the postinfarction inflammatory response and resultant repair in the mouse heart shares many common characteristics with large mammalian species, but has distinct temporal and qualitative features. These important species-specific differences should be considered when interpreting findings derived from studies using genetically altered mice.
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PMID:Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. 1474 70

Previous studies have revealed that members of the transforming growth factor-beta (TGF-beta) including TGF-beta1 and activin A modulate the function of mast cells. Here we show the up-regulation of mouse mast cell protease-6 (mMCP-6), which is expressed in differentiated mast cells, by TGF-beta1 and activin A in bone marrow-derived cultured mast cell progenitors (BMCMCs). Quantitative real time RT-PCR analyses revealed that the mRNA level of mMCP-6 was slightly but reproducibly increased by treatment with TGF-beta1 or activin A, which was regulated at the transcription level. Reporter assays showed that Smad3, a signal mediator of the TGF-beta/activin pathway, was responsible for the transcription. The TGF-beta response element is located at -153 bp relative to the transcription initiation site, CAGA. Microphthalmia-associated transcription factor (MITF), a tissue-specific transcription factor predominantly expressed in mast cells, melanocytes, the heart and skeletal muscle, also stimulated the transcription of mMCP-6. The region at -166 bp, GACCTG, was responsible for MITF-induced transcription. Mutations of the CAGA motif and the MITF responsive site indicated that the MITF site of mMCP-6 promoter is indispensable for the transcriptional activation by a constitutively active TGF-beta receptor (ALK5-TD), whereas the CAGA motif is dispensable for transcription by MITF. Transcriptional activation of mMCP-6 by the TGF-beta pathway was differently interacted with that by MITF isoform; ALK5-TD further enhanced MITF-E-induced transcription, whereas MITF-M-induced transcription abolished responsiveness to ALK5-TD. The positive regulation of mMCP-6 by the TGF-beta/activin pathway and the differential regulation by the MITF isoform suggest a rigorous regulation of mast cell function as effector cells of immune response.
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PMID:Up-regulation of mouse mast cell protease-6 gene by transforming growth factor-beta and activin in mast cell progenitors. 1545 Oct 32

Correlative data suggest that mast cells adversely affect cardiac transplantation. This study uses a mast cell-deficient rat model to directly address the role of mast cells in cardiac allotransplantation. Standardized cardiac heterotopic transplantation with cyclosporine immunosuppression was performed in mast cell-deficient and mast cell-competent rats. Rejection, ischemia, fibrosis, fibrin deposition, numbers of T-cell receptor alpha/beta positive cells, expression of transforming growth factor-beta (TGF-beta), and of endothelin-1 (ET-1) and its receptors ETA and ETB were assessed. Differences in baseline cardiac gene expression were quantified by real-time PCR in a separate group of untransplanted animals. Baseline cardiac gene expression levels of all investigated growth factors, cytokines, ET-1, ETA, and ETB were similar in mast cell-deficient and mast cell-competent rats. Surprisingly, upon heterotopic transplantation, donor heart survival was significantly reduced in mast cell-deficient rats. Moreover, in mast cell-deficient donor hearts rejection was more severe, although nonsignificant, and extracellular matrix associated TGF-beta immunoreactivity was significantly lower than in mast cell-competent donor hearts. Fibrin immunoreactive area, on the other hand, was only increased in mast cell-deficient donor hearts, but not in mast cell-competent donor hearts. Histopathological changes in all donor hearts were accompanied by increased immunoreactivity for ET-1. In conclusion, this study shows that mast cells play a protective role after cardiac transplantation.
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PMID:Influence of mast cells on outcome after heterotopic cardiac transplantation in rats. 1729 Dec 19

Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 +/- 0.6 in the vehicle group versus 4.0 +/- 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 +/- 0.1 versus 0.5 +/- 0.03; P < 0.0001), and intestinal wall thickening (842 +/- 66 microm versus 643 +/- 54 microm; P = 0.02), reduced postradiation transforming growth factor-beta overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic.
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PMID:Local administration of interleukin-11 ameliorates intestinal radiation injury in rats. 1790 60

Mast cell-fibroblast interactions may contribute to fibrosis in asthma and other disease states. Fibroblast contraction is known to be stimulated by coculture with the human mast cell line, HMC-1, or by mast cell-derived agents. Matrix metalloproteinases (MMPs) can also mediate contraction, but the MMP-dependence of mast cell-induced fibroblast contractility is not established, and the consequences of mast cell activation within the coculture system have not been fully explored. We demonstrate that activation of primary human mast cells (pHMC) with IgE receptor cross-linking, or activation of HMC-1 with C5a, enhanced contractility of human lung fibroblasts in a three-dimensional collagen lattice system. This enhanced contractility was inhibited by the pan-MMP antagonist, batimastat, and was transferrable in the conditioned medium of activated mast cells. Exogenously added MMPs promoted gel contraction by mediating the proteolytic activation of latent transforming growth factor-beta (TGF-beta). Consistent with this, fibroblast contraction induced by mast cell activation was enhanced by addition of excess latent TGF-beta to the cultures. Batimastat inhibited this response, suggesting that MMPs capable of activating latent TGF-beta were released following mast cell activation in coculture with fibroblasts. Collagen production was also stimulated by activated mast cells in an MMP-dependent manner. MMP-2 and MMP-3 content of the gels increased in the presence of activated mast cells, and inhibition of these enzymes blocked the contractile response. These findings demonstrate the MMP dependence of mast cell-induced fibroblast contraction and collagen production.
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PMID:MMP dependence of fibroblast contraction and collagen production induced by human mast cell activation in a three-dimensional collagen lattice. 1906 Feb 29

Allergic asthma is a chronic inflammatory disease mediated by T helper (Th)2 cell immune responses. Currently, immunotherapies based on both immune deviation and immune suppression, including the development of recombinant mycobacteria as immunoregulatory vaccines, are attractive treatment strategies for asthma. In our previous studies, we created a genetically recombinant form of bacille Calmette-Guerin (rBCG) that expressed Der p2 of house dust mites and established that it induced a shift from a Th2 response to a Th1 response in naive mice. However, it is unclear whether rBCG could suppress allergic airway inflammation in a mouse model. In this article we report that rBCG dramatically inhibited airway inflammation, eosinophilia, mucus production and mast cell degranulation in allergic mice. Analysis of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) levels in bronchoalveolar lavage fluid (BALF) and lung tissue revealed that the suppression was associated with a shift from a Th2 response to a Th1 response. At the same time, rBCG induced a CD4(+) CD25(+) Foxp3(+) T-cell subtype that could suppress the proliferation of Th2 effector cells in vitro in an antigen-specific manner. Moreover, suppression of CD4(+) CD25(+) T cells could be adoptively transferred. Thus, our results demonstrate that rBCG induces both generic and specific immune responses. The generic immune response is associated with a shift from a Th2 to a Th1 cytokine response, whereas the specific immune response against Der p2 appears to be related to the expansion of transforming growth factor-beta (TGF-beta)-producing CD4(+) CD25(+) Foxp3(+) regulatory T cells. rBCG can suppress asthmatic airway inflammation through both immune deviation and immune suppression and may be a feasible, efficient immunotherapy for asthma.
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PMID:Suppression of allergic airway inflammation in a mouse model by Der p2 recombined BCG. 1919 2


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