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)

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused by bronchial colonization with Aspergillus fumigatus that affects approximately 10% of patients with cystic fibrosis (CF). The diagnosis in CF patients is difficult because the cardinal symptoms of ABPA occur frequently in CF, ie, pulmonary infiltrates and wheezing, as well as the frequent colonization with A fumigatus that leads to humoral reactivity. If left untreated, ABPA leads to bronchiectasis and pulmonary fibrosis. The pathogenesis of ABPA seems to be a prolonged asthmatic late-phase reaction orchestrated by CD4+ Th2-like T cells in response to persistent pulmonary A fumigatus allergen exposure. Thus, polyclonal and A fumigatus-specific IgE antibodies (and IgA and IgG) and blood pulmonary eosinophilia are stimulated by Th2-derived cytokines such as IL-4 and IL-5. In addition, IL-4 would also promote pulmonary transendothelial migration of eosinophils, basophils, and lymphocytes via induction of cell adhesion molecules and their ligands. IgE mast cell interactions would also contribute to the bronchial reactivity and inflammation. Recent advances have begun to identify immunodominant A fumigatus allergens. Evaluation of the quantity of IgE antibodies (and IgA and IgG) and T-cell cytokine responses to specific A fumigatus allergens should aid in the diagnosis and immunopathogenesis of ABPA, especially in CF patients.
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PMID:Allergic bronchopulmonary mycosis complicating cystic fibrosis. 147 42

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.
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PMID:The effects of cyclosporin A on non-T cell components of the immune system. 150 9

Although transcription of mast cell (MC) secretory granule neutral protease genes has been shown to distinguish MC subclasses in mucosal and serosal environments, the specific cytokines that regulate the expression of these genes have not been determined. To examine cytokine-mediated gene regulation, bone marrow-derived MC (BMMC) differentiated in vitro were obtained by culturing mouse bone marrow progenitor cells in the presence of WEHI-3 cell-conditioned medium, concanavalin A-stimulated splenocyte-conditioned medium (BMMCC), or recombinant (r) interleukin (IL)-3 (BMMCIL-3). All three populations of BMMC expressed the serosal MC-specific transcripts that encode mouse MC serine protease (MMCP)-5, MMCP-6, and MC carboxypeptidase A. However, only BMMCC contained MMCP-2 mRNA, a late expressed gene selectively transcribed by intestinal mucosal MC that proliferate during helminthic infestation in response to the T cell-derived cytokines IL-3, IL-4, and IL-10. When BMMCIL-3 were exposed to rIL-10 in the presence of either rIL-3 or rIL-4, they expressed MMCP-2 mRNA. Not only was the transcription of the MMCP-2 gene in BMMC dependent on continuous exposure of the cells to rIL-10, but the level of MMCP-2 mRNA in these cells could be down-regulated by rIL-3. These studies comparing the effects of two cytokines on the transcriptional regulation of secretory granule protease genes in MC demonstrate that rIL-10 induces BMMCIL-3 to express the mucosal MC protease MMCP-2, that rIL-3 attenuates the rIL-10-induced expression of this gene, and that transcription of the MMCP-2 gene is reversed in the absence of rIL-10.
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PMID:Transcriptional regulation of the mucosal mast cell-specific protease gene, MMCP-2, by interleukin 10 and interleukin 3. 156 97

Cell recognition molecules play a crucial role in the regulation of immune cells. We recently found that mast cells (MCs) express leukocyte recognition molecules, including ICAM-1 antigen, a natural ligand of LFA-1. We here report that interleukin 4 (IL-4), a pleiotropic cytokine and mast cell differentiation factor, selectively promotes expression of surface ICAM-1 antigen and ICAM-1 mRNA in human MCs. IL-4 also up-regulates ICAM-1 antigen in cells of monocyte/macrophage lineage but has no effect on ICAM-1 antigen expressed on basophils, fibroblasts, or lymphocytes. The increase in expression of mast cell/macrophage ICAM-1 antigen induced by IL-4 may contribute to the accumulation of leukocytes and facilitate cell-contact-dependent regulation of immune cells in inflamed tissues.
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PMID:Interleukin 4 promotes expression of mast cell ICAM-1 antigen. 167 30

Nerve growth factor (NGF) is a neurotropic polypeptide which has broad biological activity other than support of growth and survival of sympathetic, sensory and central neurons. NGF promotes rat mast cell hyperplasia in vivo and human granulopoiesis in vitro, selectively augmenting basophil/mast cell differentiation in the presence of T cells or conditioned medium derived from a human T cell line (Mo-CM), a source of granulocyte-macrophage colony-stimulating factor (GM-CSF). NGF also synergizes with GM-CSF to promote human basophil/mast cell differentiation in both methylcellulose and suspension cultures of myeloid progenitors. In the current studies, we examined the interactions of NGF and several cytokines considered to be involved in human basophil/mast cell and eosinophil growth and differentiation, including interleukin (IL)-3, IL-4, IL-5, GM-CSF and granulocyte colony-stimulating factor (G-CSF). NGF synergistically enhanced IL-5 induced dose-dependent increases in histamine content and basophilic cell differentiation of myeloid leukemic HL-60 cells, but was only additive to similar effects of IL-3. In contrast, IL-4 and G-CSF did not promote basophilic differentiation of HL-60 cells in the presence or absence of NGF. Various combinations of GM-CSF, G-CSF, IL-3, IL-4 and IL-5 could not reproduce the synergy observed between NGF and either IL-5 or GM-CSF. NGF appears to represent a class of lineage-specific co-factors, in this case being involved in GM-CSF- or IL-5-induced basophilic lineage differentiation, thus contributing to tissue inflammation or repair.
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PMID:Interactions of hemopoietic cytokines on differentiation of HL-60 cells. Nerve growth factor is a basophilic lineage-specific co-factor. 169 Jan 80

Using a monoclonal antibody to the interleukin 3 (IL-3) receptor (anti-Aic2), we isolated a cDNA (AIC2B) from a mouse mast cell line which is homologous to the previously characterized gene for the IL-3 receptor (AIC2A). This cDNA encodes a polypeptide of 896 amino acid residues and has 91% amino acid sequence identity with the IL-3 receptor. A consensus sequence defining an additional cytokine receptor family is present in this clone. Compared to the AIC2A clone, the AIC2B cDNA encodes a protein with amino acid substitutions, insertions, and deletions dispersed throughout the entire protein. Oligonucleotide probes specific for each cDNA hybridized with different genomic fragments, indicating that the AIC2A and AIC2B proteins are encoded by two distinct genes. Fibroblasts transfected with the AIC2B cDNA expressed the protein at the cell surface as determined by binding with the anti-Aic2 antibody but did not bind IL-3 or other cytokines, including IL-2, IL-4, granulocyte-macrophage colony-stimulating factor, erythropoietin, and IL-9 (p40) at concentrations between 1 and 10 nM. An S1 nuclease protection assay was used to discriminate between the AIC2A and AIC2B transcripts. We found that the AIC2B gene was coexpressed with the AIC2A gene. These results suggest a potential involvement of AIC2B in cytokine signal transduction.
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PMID:Cloning and expression of a gene encoding an interleukin 3 receptor-like protein: identification of another member of the cytokine receptor gene family. 169 79

Mice with W mutations characterized by hypopigmentation, sterility, anemia, and mast cell deficiency have abnormalities in c-kit, a receptor with tyrosine kinase activity. Recently, the ligand for c-kit was cloned by investigators in several laboratories. Zsebo et al identified and cloned a gene for a cytokine termed stem cell factor (SCF) in the medium conditioned by buffalo rat liver cells, and this cytokine proved to be c-kit ligand. We have examined the effects of recombinant rat SCF (rrSCF) on colony formation from primitive hematopoietic progenitors in culture. rrSCF and erythropoietin (Ep) supported formation of granulocyte/macrophage (GM) colonies as well as a small number of multilineage and blast cell colonies from marrow cells of normal mice. We then examined the effects of rrSCF using marrow and spleen cells of mice that had been treated with 150 mg/kg 5-fluorouracil (5-FU). Unlike single factors, combinations of factors such as rrSCF plus interleukin-3 (IL-3), rrSCF plus IL-6, and rrSCF plus granulocyte colony-stimulating factor (G-CSF) markedly stimulated the growth of multilineage colonies. In contrast to these factor combinations and a combination of IL-3 and IL-6, a combination of rrSCF and IL-4 did not support multilineage colony formation. Mapping studies of the development of multipotential blast cell colonies further indicated that rrSCF, like IL-6, G-CSF, and IL-11, shortens the dormant period in which the stem cells reside. When we tested the effects of rrSCF using pooled blast cells, which are highly enriched for progenitors and are devoid of stromal cells, rrSCF plus Ep supported formation of only a few multilineage colonies, indicating that rrSCF itself is ineffective in support of the proliferation of multipotential progenitors. However, rrSCF supported formation of a significant number of neutrophil and neutrophil/macrophage colonies from pooled blast cells, indicating that rrSCF is able to support directly the proliferation of progenitors in neutrophil/monocyte lineages. c-kit ligand may play important roles in adult hematopoiesis.
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PMID:Enhancement of murine blast cell colony formation in culture by recombinant rat stem cell factor, ligand for c-kit. 171 19

IL-3 dependent mast cell lines produce cytokines in response to Fc receptor cross-linkage or to ionomycin. In this study we have observed that cells pre-cultured in IL-3 produce 10-100 times more cytokine after receptor cross-linkage in comparison with IL-4 pre-cultured cells. Although several hematopoietin receptors, including those for IL-3, IL-4 and EPO, do not contain tyrosine kinase domains, their occupancy with ligand causes tyrosine phosphorylation of specific cellular substrates. Therefore, the contribution of tyrosine kinase activation to the ability of an IL-3 dependent mast cell line, CFTL-15, to produce cytokines was analyzed. The CFTL-15 cells were transfected with growth factor receptors containing ligand-inducible tyrosine kinase domains (EGFR and PDGFR, and CSF-IR) or with the EPOR. All of the transfectants were able to proliferate in response to IL-3 or to their respective growth factor and to produce IL-3 in response to IgE receptor cross-linkage. Stimulation of the EGFR and PDGFR transfectants with their respective ligands resulted in the production of IL-3, IL-6, and GM-CSF. Stimulation of the CSF-1R or EPOR transfectants with growth factor alone failed to induce cytokine production. However, in co-stimulation assays each of the growth factors enhanced the amount of cytokine produced in response to Fc epsilon RI cross-linkage. The ability of these stimuli to induce tyrosine phosphorylation in the transfectants was analyzed. Fc epsilon RI cross-linkage in the transfectants routinely induced the tyrosine phosphorylation of 145, 86 and 72 kDa proteins, with occasional phosphorylation of 55, 52, and 40 kDa proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ligand stimulation of transfected and endogenous growth factor receptors enhances cytokine production by mast cells. 171 40

Mast cells originate from pluripotential cells in the bone marrow. Specifically, human mast cells originate from CD 34-positive progenitor cells. Mast cell proliferation requires IL-3. In the mouse, additional mast cell growth is achieved by the addition of IL-4, and GM-CSF prevents mast cell proliferation. Early bone-marrow-derived mast cells can be identified by their IgE receptors, although they may not yet have the characteristic morphology of mature mast cells. Whether these early cells may by themselves have a physiologic role, remains to be determined. Mast cells persist in culture on fibroblast monolayers, in part due to the production of soluble factor(s) from the fibroblasts themselves. Final mast cell phenotype appears dependent upon the local tissue environment.
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PMID:Early development of mast cells. 171 81

The c-kit proto-oncogene encodes the receptor for a novel hemopoietic cytokine, termed stem cell factor (SCF) or mast cell growth factor (MGF) according to its stimulating spectrum. The human receptor for SCF/MGF is expressed in a subset of normal bone marrow progenitor cells, in leukemic myeloid cells, and in mast cells. In the present study, the effects of recombinant human growth regulators (IL-1 through -9, granulocyte-macrophage/granulocyte/macrophage-CSF, IFN, and TNF) on c-kit proto-oncogene product expression were analyzed by indirect immunofluorescence, by using the anti-SCF/MGFR mAb YB5.B8, and Northern blot analyses, by using a c-kit oligonucleotide probe. Of all cytokines tested, IL-4 was found to down-regulate expression of YB5.B8 Ag in the human mast cell line HMC-1 (maximum inhibition, 51.05 +/- 16.36% mean fluorescence intensity of control; p less than 0.02), as well as in primary leukemic myeloid cells. IL-4 was also found to down-regulate expression of YB5.B8 Ag in normal enriched bone marrow progenitor cells. The effects of IL-4 on expression of YB8.B8 Ag in myeloid/mast cell progenitors was dose and time dependent (maximum effects observed on days 2 and/or 4, by using 50 U/ml of rIL-4) and could be neutralized by using anti-IL-4 mAb. Moreover, IL-4 was found to down-regulate expression of c-kit mRNA in leukemic myeloid cells as well as in HMC-1 cells. Together, these observations identify IL-4 as a regulator of c-kit proto-oncogene product expression in the human system. The effects of IL-4 on human hemopoietic progenitor cells and mast cells may be mediated in part through regulation of SCF/MGFR expression.
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PMID:IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells. 172 42


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