Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

BSF-1/interleukin-4, a product of activated T cells, has multiple biological activities that affect cells of most hematopoietic lineages. Among these is the ability of BSF-1 to costimulate the growth of mast cells and regulate the production of IgE. We demonstrate here that BSF-1 mRNA is expressed by a majority of transformed mast cell lines and by 5 IL-3-dependent non-transformed mast cell lines. BSF-1 activity, including the ability to enhance the growth of IL-3-dependent mast cells, was detected in the supernatants of transformed mast cells. The role of BSF-1 as a mast cell growth factor, its constitutive production by transformed mast cells, and the lack of IL-3 production by most of these cells raise the possibility that BSF-1 may act as an autocrine growth factor for some transformed mast cells. Furthermore, production of BSF-1 mRNA by nontransformed cells indicates that mast cells may be an important physiologic source of this factor.
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PMID:B cell stimulatory factor-1/interleukin-4 mRNA is expressed by normal and transformed mast cells. 349 23

Activation of phosphatidylinositol (PI) 3-kinase is a common sequel to tyrosine kinase activation and appears to be essential for tyrosine kinases to induce proliferation. Since multiple hemopoietic growth factors activate tyrosine kinases, we investigated whether these growth factors activate PI 3-kinase. We show that interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), granulocyte-macrophage colony stimulating factor (GM-CSF), and steel factor (SLF) all activate PI 3-kinase. These cytokines increased the amount of PI 3-kinase activity that could be immunoprecipitated with anti-phosphotyrosine antibodies from the MC-9 mast cell line or from the hemopoietic progenitor cell line FDC-P1. Increases in this assay frequently correlate with PI 3-kinase activation in vivo. To determine directly whether these factors activate PI 3-kinase in vivo, we measured the levels of 3-phosphorylated inositol phospholipids in intact 32P-labeled MC-9 cells. IL-3, IL-4, IL-5, GM-CSF, and SLF all caused increased synthesis of the PI 3-kinase products phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with a relative potency of SLF >> IL-3 > IL-5, GM-CSF > IL-4. In contrast, IL-4 caused the largest increase in the in vitro anti-phosphotyrosine immune complex PI 3-kinase assay. Thus, the in vitro assay does not accurately reflect in vivo activation of PI 3-kinase. Cytokine treatment did not stimulate tyrosine phosphorylation of either the 85-kDa regulatory subunit or the 110-kDa catalytic subunit of PI 3-kinase and is therefore not required for activation of PI 3-kinase by these factors. Cytokine treatment did induce PI 3-kinase to associate with other tyrosine-phosphorylated proteins in a cytokine-specific manner. PI 3-kinase associated with c-kit after SLF stimulation, a 170-kDa protein after IL-4 stimulation, and a 70-kDa protein after treatment with IL-3 or GM-CSF. Thus, multiple hemopoietic growth factors that act through different types of receptors activate PI 3-kinase in vivo and induce factor-specific interactions of PI 3-kinase with other tyrosine-phosphorylated proteins.
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PMID:Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins. 750 38

Steel (SI) and white spotting (W) loci encode steel factor (c-kit ligand) and the c-kit tyrosine kinase receptor, respectively. Mutations at these loci affect migration and differentiation of primordial germ cells, neural crest-derived melanoblasts, and hematopoietic cells. In these processes, cell adhesion molecules are hypothesized to be crucial. We have examined the role of steel factor and c-kit in cell-extracellular matrix adhesion using bone marrow-derived mast cells as a model system. Steel factor stimulates mast cells to bind to fibronectin and, to a lesser extent, to vitronectin, whereas interleukin-3 and interleukin-4, which are also mast cell growth factors, do not. Activation of adhesiveness is transient, occurs at concentrations of steel factor 100-fold lower than required for growth stimulation, and requires the integrin VLA-5. Mast cells from c-kit mutant mice adhere to fibronectin on stimulation with phorbol 12-myristate 13-acetate (PMA), but not on stimulation with steel factor, indicating that stimulation of integrin adhesiveness requires activation of the c-kit protein tyrosine kinase. By contrast, c-kit mutant and wild-type mast cells adhere equally well to COS cells expressing membrane-anchored steel factor, showing that the kinase activity of c-kit is not required for adhesion directly mediated by c-kit. Our findings suggest that regulation of adhesion is an important biologic function of steel factor.
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PMID:Steel factor and c-kit regulate cell-matrix adhesion. 750 7

Although interleukin-4 (IL-4) in mice is known to augment the proliferation of mast cells and to modulate the expression of certain mast cell protease transcripts, its effect on human mast cells is less well understood. The current study examined the effects of recombinant human IL-4 (rhuIL-4) on stem cell factor (SCF)-dependent fetal liver-derived human mast cells in liquid culture. In no case did rhuIL-4 augment proliferation of mast cells. rhuIL-4 selectively inhibited certain aspects of the development of mast cells in cultures of fetal liver cells with rhuSCF. These include lower numbers and percentages of cells expressing tryptase and surface Kit, smaller cells, and lower contents of cells for tryptase, histamine, and Kit. Development of metachromasia was not attenuated. The downregulation of Kit, the surface receptor for SCF, is probably a critical factor, because cells lacking this molecule would not be able to respond to SCF. In contrast to mast cell progenitors, mast cells already developed in vitro from fetal liver cells are relatively resistant to rhuIL-4, but are still dependent for survival on the presence of rhuSCF.
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PMID:Interleukin-4 inhibits the expression of Kit and tryptase during stem cell factor-dependent development of human mast cells from fetal liver cells. 752 Jul 76

Stem cell factor (SCF) possesses many mast cell-stimulating activities, including the ability to support the growth of mucosal-like mast cells (MMCs) and connective tissue mast cells (CTMCs). However, this study shows that, in the absence of accessory cells, SCF does not stimulate the clonal growth of primitive mast cell progenitors. Nevertheless, SCF exhibited potent growth-promoting effects when combined with the cytokines interleukin-3 (IL-3), interleukin-4 (IL-4), and interleukin-10 (IL-10). Our comparative studies have shown that optimal mast cell colony formation occurs when both IL-4 and IL-10 are combined with SCF. However, in the presence of SCF, these two cofactors appear to mediate different effects. IL-4 was more efficient than IL-10 in costimulating the initiation of SCF-dependent colony formation by mast cell progenitors and in sustaining the proliferation of newly generated progeny. On the other hand, IL-4 was less efficient than IL-10 in supporting mast cell differentiation, as evidenced by morphology, cell enlargement, and granule production. Although the actions of IL-4 and IL-10 were not equivalent, additional experiments indicated that their ability to serve as early- and late-acting factors, respectively, were complimentary. We have also found that the mast cells generated in colonies stimulated by IL-4, IL-10, and SCF produced high levels of histamine (6-8 pg per cell). None of the mast cells generated in our cultures synthesized heparin. A phenotypic change from safranin-negative to safranin-positive cells associated with heparin-producing CTMCs was accomplished after coculture of the mast cells with fibroblast cell lines derived from normal mice or from SI/SId mice plus soluble factors. Collectively, our observations demonstrate that SCF acts as a competence factor for mast cell progenitor growth. In addition, the ability of SCF to support certain stages of mast cell differentiation is profoundly influenced by interactions with specific cofactors.
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PMID:Cofactors are essential for stem cell factor-dependent growth and maturation of mast cell progenitors: comparative effects of interleukin-3 (IL-3), IL-4, IL-10, and fibroblasts. 752 73

Human mast cells and basophils participate in allergic inflammation by releasing preformed and newly synthesized mediators upon cross-linking of cell surface IgE/receptor complexes with specific antigen. It is becoming increasingly apparent, however, that the basophil response is up-regulated by a far greater number of cytokines than is the mast cell, making the basophil more sensitive to products that are commonly generated during immune reactions. As a result, basophils may have a greater role in the chronic allergic inflammation that characterizes diseases such as asthma. This belief is supported further by the fact that the basophil has recently been shown to generate interleukin-4, and possibly other cytokines, indicating a role for this cell in directing the immune response of other cell participating in allergic lesions.
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PMID:The interaction of cytokines with human basophils and mast cells. 754 7

By using the reverse transcriptase (RT)-PCR and in situ hybridization we have studied the expression of mRNA for IL-5 and IL-4 in human lung mast cells induced by cross-linkage of high affinity Fc epsilon Rs. Lung mast cells were purified using affinity magnetic selection with mAb YB5.B8 against c-kit to achieve a final mast cell purity > 93%. Purified mast cells were precultured with stem cell factor (SCF) (10 ng/ml) and myeloma IgE (3 micrograms/ml) for 16 h before challenge with anti-IgE (1 or 10 micrograms/ml). IgE-dependent activation of lung mast cells caused expression of IL-5 mRNA, which was evident by 2 h and persisted for up to 48-72 h in all of 12 experiments, whereas IL-4 mRNA expression was of a shorter duration and was demonstrable in 6 of 13 experiments. We confirmed that mast cells, and not T cells, were the source of these cytokine messages by using reverse transcriptase-PCR in cell preparations containing known numbers of mast cells and T cells, in situ hybridization in enriched mast cell preparations, and double in situ hybridization-immunocytochemical staining. IL-5 mRNA expression did not require the pretreatment of cells with SCF, whereas expression of IL-4 mRNA seemed to require both anti-IgE and SCF. The strength of IL-5 mRNA signal was related to anti-IgE concentration. Immunoreactive IL-5 was detectable 8 h after anti-IgE challenge, and 10(6) mast cells generated a mean of 731 +/- 400 pg of IL-5 into the supernatant during 48-h culture, but no IL-4 product was detectable. These findings demonstrate the capacity of human lung mast cells to transcribe IL-4 and IL-5 after IgE-dependent activation and to synthesize and release immunoreactive IL-5.
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PMID:IgE-dependent expression of mRNA for IL-4 and IL-5 in human lung mast cells. 754 33

The late-phase of allergic asthma is characterized by infiltration of the airway with eosinophils within 6 h of mast cell activation. Pro-eosinophilic/pro-allergic (TH2) cytokines, originally described as T-lymphocyte products, have recently been ascribed to mast cells as well. To date, however, it is unknown if TH2 cytokine gene expression by the human mast cells is subject to receptor-mediated regulation analogous to that of T-cells, and if messenger RNA (mRNA) expression results in protein secretion occurring in a temporal context consistent with the late-phase response. We examined interleukin-4 (IL-4), IL-5, and IL-6 mRNA expression induced by anti-IgE activation of human lung explants as assessed using reverse transcription/polymerase chain reaction (RT-PCR). Anti-IgE stimulation resulted in rapid and sustained upregulation of IL-5 message, but did not have analogous effects on IL-4 or IL-6. Using quantitative-competitive PCR, we demonstrated that 100 ng of total cellular RNA from human lung contained 1 fg of IL-5 mRNA; this increased to 100 fg 4 h after anti-IgE activation. The source of the anti-IgE-enhanced IL-5 mRNA is likely the mast cell itself, as anti-CD3 activation of lung led to a dissimilar array of cytokine expression. In addition, human lung mast cells purified to near homogeneity expressed IL-5 mRNA after activation, as shown by both RT-PCR and in situ hybridization. In both lung fragments and purified human lung mast cells, the modulation of IL-5 mRNA expression preceded the secretion of IL-5 protein, detected as early as 4 h after activation. Neither isolated purified mast cells nor purified peripheral blood T cells could be induced to secrete detectable amounts of IL-5 protein when activated only with antibodies against IgE or CD3-T cell receptor complex, respectively. However, mast cells (n = 4) and T cells (n = 6) cultured at comparable concentrations (4 x 10(6)/ml) activated through their respective antigen receptors in the presence of phorbol ester yielded comparable IL-5 production (253 +/- 126 pg/ml versus 183 +/- 75 pg/ml, mean +/- SE). We conclude that mast cells are analogous to T cells in the requirement of co-stimuli for the production of IL-5 protein. Moreover, the rapid kinetics of IgE-mediated IL-5 transcription and protein elaboration are consistent with a primary role for mast cell activation directly leading to late-phase airway eosinophilia.
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PMID:Human lung mast cell IL-5 gene and protein expression: temporal analysis of upregulation following IgE-mediated activation. 757 4

Although the immune responses to intestinal nematode infection have been well studied and have been shown to be strongly driven by Th2-associated cytokines in mice, such information has been limited with respect to rats. We investigated changes in levels of the mRNAs encoding interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-10, and gamma interferon in the mesenteric lymph nodes of rats infected with Nippostrongylus brasiliensis by reverse transcription-PCR in comparison with immunoglobulin E (IgE)/IgG2a antibody, eosinophil, basophil, and mucosal mast cell responses. In the two rat strains used, Brown Norway and Fischer-344, which show different responses to allergens, serum IgE increased to much higher levels in the former than in the latter 2 weeks after infection. Intestinal mastocytosis was observed much earlier and more intensely in Brown Norway rats than in Fischer-344 rats, but the degrees of peripheral eosinophilia and basophilia did not differ between the two strains. In both strains, IL-3, IL-4, and IL-5 mRNA expression increased and peaked around 7 to 14 days after infection, while expression of IL-2, IL-10, and gamma interferon mRNAs did not change notably throughout the experimental period. The highest IL-4 mRNA expression was observed slightly earlier in Brown Norway than in Fischer-344 rats, but levels of IL-3 and IL-5 mRNAs peaked synchronously in both strains. The amounts of mRNAs encoding these three cytokines were always higher in Brown Norway than in Fischer-344 rats. It is suggested that in rats, Th2 or Th2-like cells are also induced after nematode infection, and IgE elevation is mainly related to increased IL-4 gene expression.
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PMID:Cytokine mRNA expression profiles in rats infected with the intestinal nematode Nippostrongylus brasiliensis. 759 Nov 19

In both seasonal and perennial rhinitis there is epithelial mast cell accumulation and tissue infiltration by eosinophils. Activation of these cells can be observed by electron microscopy and by elevated levels of tryptase and eosinophil cationic protein in nasal lavage fluid. Furthermore, seasonal increases in the antigen presenting cell (Langerhans' cell) are also evident. Investigations into the mechanisms involved in cell accumulation and activation reveals upregulation of leucocyte endothelial adhesion molecules and an increase in interleukin-4 (IL-4) in naturally occurring rhinitis, while mRNA for IL-4, IL-5 and granulocyte macrophage colony stimulating factor activity and lavage tumour necrosis factor-alpha (TNF alpha) levels are increased following local allergen challenge. These cytokines may be derived from a variety of sources, including mast cells, eosinophils and T-lymphocytes, and contribute to the underlying inflammatory process in rhinitis.
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PMID:The cellular basis for allergic rhinitis. 760 53


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