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 cell infiltration and accumulation is known to occur in tissue fibrosis. Increased numbers of mast cells are detected in scleroderma or hypertrophic scar skin, however, neither the role of mast cells nor the interaction of fibroblasts and mast cells in fibrosis are fully understood. A growing body of evidence indicate that mast cells are rich source of cytokines, growth factors or chemokines, which are suggested to play an important role in the induction of fibrosis. Recent in vivo and in vitro studies suggest the involvement of monocyte chemoattractant protein-1 (MCP-1), a member of the C-C chemokine family, in fibrosis. Here, we examined the effect of stem cell factor (SCF), a mast cell growth factor, on MCP-1 gene expression in a human mast cell line, HMC-1, and as well as the effect of MCP-1 on alpha1(I) collagen gene expression in human skin fibroblasts. HMC-1 cells spontaneously expressed MCP-1 mRNA transcripts, which was detectable by in situ hybridization and Northern blot analysis. Stimulation with SCF further upregulated MCP-1 mRNA expression in a time- and dose-dependent manner, and stimulation with 100 ng/ml SCF for 24 h induced a 3-fold increase of MCP-1 mRNA expression in HMC-1 cells as compared with unstimulated cells. The concentration of MCP-1 protein in the culture supernatants of 50 ng/ml SCF-stimulated HMC-1 cells (3816+/-70 pg/ml) was significantly elevated compared to unstimulated cells (2588+/-130 pg/ml) (P < 0.01), as assessed by ELISA. Adversely, MCP-1 induced alpha1(I) collagen mRNA expression in normal skin fibroblasts dose-dependently. Finally, comparative study revealed that the concentration of SCF in the culture supernatants of scleroderma fibroblasts at primary passages was significantly increased (344.6+/-182.4 pg/ml), as compared with normal skin fibroblasts (72.4+/-20.2 pg/ml) (P<0.05). These results suggest that fibroblast-derived SCF upregulates MCP-1 expression and synthesis in mast cells, which acts on fibroblasts to enhance alpha1(I) collagen mRNA expression. Our data may indicate an important interaction of fibroblasts and mast cells, via SCF and MCP-1, in the induction of fibrosis.
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PMID:Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. 1137 26

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

Chronic pancreatitis (CP) is characterized by mononuclear inflammatory cell infiltration and replacement of the destroyed parenchyma by fibrous tissue. Recently, mast cells have been implicated in chronic inflammatory processes with fibrous tissue deposition. Therefore, the number and distribution of mast cells and their state of activation were evaluated in 12 normal specimens and in 46 specimens of CP with different causes (alcoholic, tropical, and idiopathic). Furthermore, the presence of stem cell factor (SCF), the main mast cell growth factor, and of its receptor, c-kit, was also assessed. In CP tissues, mast cells were localized both in the fibrotic areas and in the residual acinar parenchyma. The total number of mast cells was significantly higher in CP than in the normal pancreas (P < .0001) and correlated positively with the extent of fibrosis and the intensity of inflammation. Immunoglobulin E (IgE)-dependent mast cell activation was higher in CP than in the normal pancreas. No differences in mast cell number or IgE positivity were found among the 3 causes of CP. SCF-and c-kit immunoreactive mast cells were mostly localized in fibrous tissue and around regenerating ducts, which were also positive for c-kit but were negative for SCF. These results suggest that mast cells, activated by an IgE-dependent mechanism and/or by an SCF-c-kit autocrine loop, are a relevant component of the inflammatory infiltrate in CP, independent of the underlying cause. Their localization near degenerating acini and regenerating ducts might indicate that they play a crucial role in tissue destruction and remodeling in CP.
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PMID:Mast cell distribution and activation in chronic pancreatitis. 1172 55

Mast cell hyperplasia is observed in various inflammatory skin diseases. Although the mechanisms involved in the pathogenesis of these conditions remains largely uninvestigated, it is speculated that mediators produced in the lesional skin provide a favorable microenvironment for mast cell growth. Among the proinflammatory mediators, leukemia inhibitory factor (LIF), which shares a receptor component (gp130 subunit) with interleukin-6 (IL-6), has been identified as a mast cell growth-enhancing factor produced by cells of the keratinocyte-derived cell line (KCMH-1). In this study, we investigated the effect of four IL-6 family cytokines, IL-6, IL-11, oncostatin M (OSM) and LIF on mast cell growth in a mast cell/fibroblast co-culture system. When mouse bone marrow-derived cultured mast cells (BMMC) were maintained on a NIH/3T3 fibroblast monolayer, these cytokines induced proliferation of the mast cells, but none of the cytokines had any effect on mast cell proliferation in the absence of fibroblasts. mRNA for gp130 and receptors for the four IL-6 family cytokines were detected in NIH/3T3 fibroblasts by reverse transcriptase-mediated polymerase chain reaction. In contrast, only mRNA for the IL-11 receptor and gp130 were detected in BMMC. Tyrosine phosphorylation of gp130 was observed in NIH/3T3 fibroblasts after stimulation with all the cytokines. Some IL-6 family cytokines enhanced the production of stem cell factor (SCF), a potent mast cell growth factor, from NIH/3T3 fibroblasts, but the amount of SCF produced by NIH/3T3 fibroblasts was not paralleled by the mast cell growth-enhancement induced by the IL-6 family cytokines. When anti-SCF antibody was added with the IL-6 family cytokines in the BMMC/fibroblast coculture system, a significant effect of these cytokines remained, although the growth-enhancing activity was markedly reduced. A similar result was obtained when BMMC were prepared from W/W(V)-mice, which lack functional c-kit, in the BMMC/ fibroblast coculture system. These results suggest that IL-6 family cytokines stimulate mast cell growth by a fibroblast-dependent mechanism, and also suggest the existence of another pathway between BMMC and NIH/3T3 fibroblasts cooperating with the SCF/c-kit pathway. IL-6 family cytokines may thus contribute to mast cell hyperplasia in skin diseases.
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PMID:The IL-6 family cytokines, interleukin-6, interleukin-11, oncostatin M, and leukemia inhibitory factor, enhance mast cell growth through fibroblast-dependent pathway in mice. 1182 Jul 27

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

Mast cells are thought to participate in a variety of immune responses, such as parasite resistance and the allergic reaction. Mast cell development depends on stem cell factor (Kit ligand) and its receptor, c-Kit. Gab2 is an adaptor molecule containing a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains. Gab2 is phosphorylated on tyrosine after stimulation with cytokines and growth factors, including KitL. Gab2-deficient mice were created to define the physiological requirement for Gab2 in KitL/c-Kit signaling and mast cell development. In Gab2-deficient mice, the number of mast cells was reduced markedly in the stomach and less severely in the skin. Bone marrow-derived mast cells (BMMCs) from the Gab2-deficient mice grew poorly in response to KitL. KitL-induced ERK MAP kinase and Akt activation were impaired in Gab2-deficient BMMCs. These data indicate that Gab2 is required for mast cell development and KitL/c-Kit signaling.
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PMID:Requirement of Gab2 for mast cell development and KitL/c-Kit signaling. 1186 9

Mast cell hyperplasia is found in different pathologies such as chronic inflammatory processes, fibrotic disorders, wound healing or neoplastic tissue transformation. The functional significance of the accumulation of mast cells in these processes is largely unknown. It is now established that bone marrow-derived mast cell progenitors circulate in peripheral blood and subsequently migrate into the tissue where they undergo final maturation under the influence of local microenvironmental factors. Cytokines are of particular importance for mast cell recruitment, development, and function. Stem cell factor (SCF) is a unique mast cell growth factor, since mast cells disappear completely in the absence of SCF. However, several other cytokines such as IL-3 and IL-4 have been shown to influence mast cell proliferation and function also. This review focuses on the role of cytokines in the regulation of mast cell hyperplasia.
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PMID:Mast cell hyperplasia: role of cytokines. 1191 20

The steel factor (SLF) and c-Kit growth factor/receptor pair are key molecules governing mast cell development and survival. SLF is expressed on stromal cells as a membrane-bound molecule (mSLF) which can be cleaved by proteases to release a soluble form (sSLF). We investigated the importance of phospholipase C (PLC) activation in mast cells stimulated by sSLF and mSLF. PLC antagonists U73122, neomycin sulfate and oleic acid inhibited mast cell thymidine incorporation stimulated by mSLF, but not by sSLF. These antagonists suppressed sSLF-induced Ca2+ transients but did not significantly interfere with c-Kit phosphorylation or PLC-gamma2 recruitment. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase), was found to be efficiently recruited to c-Kit following stimulation by sSLF or mSLF. However PKB/Akt, a kinase activated by PI3-kinase products, was phosphorylated following sSLF stimulation, but not with mSLF. Taken together, these studies demonstrate the importance of PLC activation by mSLF in supporting mast cells.
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PMID:Mast cells stimulated by membrane-bound, but not soluble, steel factor are dependent on phospholipase C activation. 1278 22

Few peribronchial mast cells are noted either in the lungs of naive mice or in the lungs of OVA-sensitized mice challenged acutely with OVA by inhalation. In this study, we demonstrate that OVA-sensitized mice exposed to repetitive OVA inhalation for 1-6 mo have a significant accumulation of peribronchial mast cells. This accumulation of peribronchial mast cells is associated with increased expression of the Th2 cell-derived mast cell growth factors, including IL-4 and IL-9, but not with the non-Th2 cell-derived mast cell growth factor, stem cell factor. Pretreating mice with immunostimulatory sequences (ISS) of DNA containing a CpG motif significantly inhibited the accumulation of peribronchial mast cells and the expression of IL-4 and IL-9. To determine whether mast cells express Toll-like receptor-9 (TLR-9; the receptor for ISS), TLR-9 expression by mouse bone marrow-derived mast cells (MBMMCs) was assessed by RT-PCR. MBMMCs strongly expressed TLR-9 and bound rhodamine-labeled ISS. However, incubation of MBMMCs with ISS in vitro neither inhibited MBMMC proliferation nor inhibited Ag/IgE-mediated MBMMC degranulation, but they did induce IL-6. Overall these studies demonstrate that mice exposed to repetitive OVA challenge, but not acute OVA challenge, have an accumulation of peribronchial mast cells and express increased levels of mast cell growth factors in the lung. Although mast cells express TLR-9, ISS does not directly inhibit mast cell proliferation in vitro, suggesting that ISS inhibits accumulation of peribronchial mast cells in vivo by indirect mechanism(s), which include inhibiting the lung expression of Th2 cell-derived mast cell growth factors.
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PMID:Accumulation of peribronchial mast cells in a mouse model of ovalbumin allergen induced chronic airway inflammation: modulation by immunostimulatory DNA sequences. 1456 66

The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation.
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PMID:Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. 1467 74


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