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)

Interleukin 3 (IL-3) is required for the survival and proliferation of mouse bone marrow derived mast cells (BMMC). Although interleukin 4 (IL-4) has no direct effect on growth activity, it synergizes with IL-3 in promoting the growth of these cells. The intracellular mechanism by which these ligand-receptor interactions promote mast cell growth are not well documented in the literature. Here we present evidence that both IL-3 and IL-4 have been found to activate protein kinase C (PKC) and phosphatidylinositol turnover in BMMC, in a similar time- and dose-dependent manner, indicating that activation of PKC is not sufficient to induce proliferation in these cells. In this work we addressed the question as to whether the activation of PKC is necessary for mast cell proliferation. Activation of PKC by phorbol myristate acetate causes inhibition of IL-3-mediated growth for the first 72 h of incubation. The inhibition in IL-3-mediated proliferation gradually lessens with the stages of PKC depletion, which is complete after 72 h. The enhancement in phorbol myristate acetate-treated cells grows as PKC is depleted. The inactive phorbol ester, 4-alpha-phorbol, had no effect on proliferation of BMMC. Cells, PKC-depleted by chronical phorbol ester treatment, responded to IL-3 or IL-4 with a significant increase in [3H] thymidine uptake over PKC containing cells stimulated with the same lymphokine. Use of antibodies to these lymphokines showed that the enhanced response of the PKC-depleted BMMC was not due to the additional autocrine production of IL-3 or IL-4 by these cells. The PKC-depleted cells retain the capacity to return to almost normal levels of PKC activity and sensitivity to IL-3 and IL-4, after 72 and 120 h, respectively. These results indicate that PKC plays an important inhibitory role in IL-3- and IL-4-mediated proliferation of BMMC.
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PMID:Protein kinase C plays an inhibitory role in interleukin 3- and interleukin 4-mediated mast cell proliferation. 226 15

A clonal marrow-adherent stromal cell line, +/+-1 LDA11, was derived and found to produce hemopoietic stimulatory activity for an interleukin 3 (IL-3)-dependent mast cell line, NFS/N1. This factor-dependent mast cell line displayed restricted growth factor responsiveness to only IL-3, interleukin 4 (IL-4), and the stromal cell-produced factor. The factor produced by stromal cells was distinguished from IL-3 and IL-4 and was characterized biochemically. This factor appears to be a novel mast cell growth factor (MCGF-3) capable of synergizing with IL-3 and IL-4. It may have broader reactivity in hemopoiesis than simply IL-3-dependent mast cells, and it may prove relevant to stromal cell-mediated hemopoiesis.
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PMID:A novel mast cell growth factor (MCGF-3) produced by marrow-adherent cells that synergizes with interleukin 3 and interleukin 4. 237 44

In response to IgE and specific multivalent antigen, mast cell lines (both growth factor-dependent and -independent) induce the transcription and/or secretion of a number of cytokines having a wide spectrum of activities. We have identified IL-1, IL-3, IL-5, IL-6, IFN-gamma, GM-CSF, JE, MIP1 alpha, MIP1 beta, and TCA3 RNA in at least two of four mast cell clones. The production of these products (except JE) is activation-associated and can be induced by IgE plus antigen. In selected instances cytokine expression can also be induced by activation with Con A or phorbol ester plus ionophore, albeit to levels less than those observed with IgE plus antigen. In addition, long-term mast cell clones and primary cultures of bone marrow-derived mast cells specifically release IL-1, IL-4, and/or IL-6 bioactivity after activation. These findings suggest that in addition to their inflammatory effector function mast cells may serve as a source of growth and regulatory factors. The relationship of mast cells to cells of the T lymphocyte lineage is discussed.
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PMID:Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. 247 61

Various human lymphokines such as semipurified human interleukin 3 (IL 3), recombinant human IL 3, granulocyte colony stimulating factor (G-CSF), and recombinant human interleukin 4 (IL 4) stimulated growth of human bone marrow cells, but from all these factors tested, only IL 3 by itself was able to cause an increase in histamine content. Fibroblast monolayers as well as factors in their supernatants also increased proliferation and histamine content of bone marrow cells. Concentrated supernatants (Mr greater than 10,000) also inhibited cell proliferation and induced histamine content. The same fraction concentrated on a Mr cut-off greater than 50,000 enhanced cell growth and the total histamine content per culture. Thus, fibroblast supernatants contained both growth promoting and inhibitory factors. However, using the rat basophilic leukemia (RBL) cell line as a test system for such fibroblast-derived differentiation factors, we showed that if cell proliferation was inhibited, histamine content was also enhanced. Furthermore, certain drugs known to inhibit cell division, such as sodium butyrate or hydroxyurea, were also found to cause an increase in histamine content of RBL cells. Thus, our data demonstrate that basophil/mast cell differentiation, in terms of augmentation of cellular histamine levels, may be achieved by exposure to certain growth-inducing cytokines, factors inhibiting proliferation or pharmacological agents which inhibit cell proliferation.
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PMID:Factors influencing proliferation and histamine content of cultured human bone marrow cells. 247 28

Mast cells are critical effectors in many IgE-dependent responses, and the numbers and phenotype of certain mast cell populations can be influenced, through IL-3 and IL-4, by the same T cells that regulate IgE production. However, IgE can interact with cells other than mast cells, and different mast cell populations express significant variation in multiple important aspects of their phenotype, including mediator content and responses to cytokines and stimuli of activation. As a result it may be difficult to define the unique contributions of mast cells to IgE-dependent reactions. One approach for analysing the roles of various mast cell populations in individual biological responses is to attempt to elicit these reactions in mice in which the presence or absence of specific mast cell populations can be regulated experimentally. We have used genetically mast cell-deficient and mast cell-reconstituted mice to demonstrate that mast cells provide essential effector function in certain IgE-dependent responses involving the skin, stomach or lungs but are not necessary for the pulmonary alterations and death associated with active anaphylaxis. Similar approaches can be used to investigate the biological significance of the production, by mast cells stimulated with IgE and specific antigen, of cytokines similar or identical to IL-1, IL-3, IL-4, IL-5, IL-6, TNF-alpha/cachectin, IFN-gamma, GM-CSF, JE, MIP-1 alpha, MIP-1 beta and TCA3.
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PMID:Mast cells: immunologically specific effectors and potential sources of multiple cytokines during IgE-dependent responses. 251 50

Figure 1 depicts some of the potential interactions of the interleukins. Among the substances discussed here, only IL-2 has been used to any large degree in a clinical series. Other cytokines not discussed including some of the colony stimulating factors, tumor necrosis factor and the interferons have also been used in clinical trials. Undoubtedly as we learn more about interleukins IL-1 through IL-7, clinical applications will become apparent. For the allergist/immunologist there are two areas of greatest potential interest. The first of these is in treating immunodeficiency states. Preliminary studies of the use of IL-2 in patients with T cell dysfunction suggest that this substance may be useful in treating selective T cell disorders. IL-4, 5, and 6 all have some influence on B cell function. It is likely that in the near future one or more of these agents will be used clinically. It is also clear that the interleukins have the potential to influence basic mechanisms known to be important in allergic disease. IL-3 is the major factor influencing mast cell growth. IL-4 among other things, promotes B cells to switch to IgE synthesis as well as to induce Fc epsilon RII receptors on B cells. IL-5 is important in the differentiation and growth of eosinophils. Finally, IL-6 is the terminal differentiation factor that causes B cells to become plasma cells. The next few years should result in an even better understanding of the role of each of these interleukins. It is likely that such information will greatly expand the horizons for understanding the pathogenesis of many immunologically mediated diseases and will provide the basis for new modalities of treatment.
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PMID:Interleukins in immunologic and allergic diseases. 267 43

The stimulatory effects of lymphokines, interleukin 3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL-4), and the inhibitory effects of transforming growth factor beta (TGF-beta) and the pertussis toxin, islet activating protein (LAP), on multi-factor-dependent myeloid cell lines were examined. The effects of IL-3 on a mast cell progenitor clone, IC2 were indistinguishable from those of GM-CSF with respect to their concentration-response curves for induction of DNA synthesis and capability to maintain cell growth for many months. IL-4 acts differently on IC2 cells: the maximum level of DNA synthesis induced by IL-4 is always lower than that induced by IL-3 or GM-CSF and IL-4-induced proliferation is transient. IL-4, however, synergistically induced DNA synthesis of IC2 cells with limiting concentrations of IL-3 or GM-CSF. When IC2 cells were cultured with saturating concentrations of IL-3, GM-CSF or a combination of both, the doubling time was 25 +/- 1 h, whereas it decreased to 17 +/- 1 h when IL-4 was further added to the cultures. IAP reduced the DNA synthesis of IC2 cells induced by the above three growth factors. The doubling time of IC2 cells was 30 +/- 2 h when IC2 cells were cultured with sufficient concentrations of IL-3 in the presence of IAP. Cell cycle analysis revealed that the fraction of cells in Gl was decreased by IL-4 but was increased by IAP. TGF-beta also reduced IL-3-dependent DNA synthesis and increased the fraction of cells in Gl. The inhibitory effect on IL-3-dependent growth of IC2 cells was not increased when these cells were exposed simultaneously to TGF-beta and IAP. The results suggest that IL-3 and GM-CSF stimulate the growth of IC2 cells through similar pathways and that IL-4 augments the action of IL-3 or GM-CSF by decreasing the Gl period. It is also suggested that IAP and TGF-beta retard the growth of IC2 cells by increasing the fraction of cells in GI.
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PMID:Growth regulation of multi-factor-dependent myeloid cell lines: IL-4, TGF-beta and pertussis toxin modulate IL-3- or GM-CSF-induced growth by controlling cell cycle length. 268 Jan 12

We have identified a late, committed stage in the differentiation of the mast cell progenitor just before granulation. Mast cell committed progenitors (MCCP) are nongranulated cells with a density of 1.060 to 1.070 g/ml which can be harvested from the mesenteric lymph node of mice infected with Nippostrongylus brasiliensis. Mast cell-committed progenitors are able to proliferate and differentiate in the absence of IL-3 or IL-4 when cultured on a monolayer of embryonic skin or 3T3 fibroblasts and can form colonies in methylcellulose supplemented with fibroblast conditioned medium. Fibroblast conditioned medium appears to contain a soluble MCCP proliferation factor that maintains biologic activity when heated to 56 degrees C for 45 min but is destroyed by incubation with either trypsin or chymotrypsin. It can be selectively precipitated with 60 to 70% saturated ammonium sulfate. The factor is not absorbed by immobilized antibodies to nerve growth factor. The MCCP proliferation activity of the factor could not be mimicked by IL-1, IL-2, IL-4, granulocyte-macrophage-CSF, granulocyte-CSF, macrophage-CSF, IFN-alpha/beta, IFN-gamma, nerve growth factor, epidermal growth factor, serum fibronectin, heparin, or a number of glycosaminoglycans. At high salt concentrations, the factor passes through a 50-kDa membrane and can be concentrated above a 5-kDa membrane. MCCP acquire a connective tissue phenotype when cultured on a fibroblast monolayer and a mucosal phenotype when cloned in the presence of conditioned medium from PWM-stimulated spleen cells. When cultured in the absence of IL-3 on a monolayer of embryonic skin or 3T3 fibroblasts, mast cell-committed progenitors produce mast cells which stain with berberine sulfate suggesting a connective tissue phenotype; however, the mast cells that develop when mast cell-committed progenitors are cultured in the presence of IL-3 or conditioned media from PWM-stimulated spleen cells do not stain with berberine sulfate. MCCP intercalate into monolayers of embryonic skin or 3T3 fibroblasts, but T cells are not able to associate with the monolayer and can be completely washed away. Attempts to enrich mast cell-committed progenitors by intercalation and elution from embryonic skin monolayers proved unsuccessful, but some enrichment of mast cell-committed progenitors could be achieved by discontinuous Percoll gradients. Thus, we have identified a way to obtain late-stage, mast cell-committed progenitors in an environment that is virtually uncontaminated with other hematopoietic progenitors.
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PMID:The mast cell-committed progenitor. I. Description of a cell capable of IL-3-independent proliferation and differentiation without contact with fibroblasts. 278 62

A series of permanent IL-3-dependent cell lines have been established from normal BALB/c or C3H bone marrow using alpha-thioglycerol-supplemented culture medium and PWM-stimulated spleen cell-conditioned medium as a source of IL-3. The cell lines and derivatives cloned in agar resembled "mucosal type" mast cells with respect to phenotypic and functional properties. In this report we demonstrate that in vitro growth of these mast cell lines was not only dependent on IL-3 and synergistically enhanced by IL-4, but in addition regulated by alpha-thioglycerol which could be replaced by 2-ME or cysteamine. We show that these thiol-sensitive mast cell lines respond to a mast cell growth enhancing activity (MEA) present in spleen cell-conditioned medium and acting in concert with IL-3. Partially purified MEA was not able to stimulate the growth of IL-3-dependent 32Dcl.23 cells, IL-2-dependent CTLL-2 cells or the mouse T cell line F4/4K.6 (L3T4+) adapted to grow in purified IL-4. Moreover, 11B11 hybridoma-derived anti-IL-4 mAb specifically neutralizing mouse Il-4 were unable to abolish the bioactivity of MEA. PWM, CSF-1, GM-CSF, IL-1, IL-2, IL-5, IL-6, IL-7, IFN-gamma, TGF-alpha, TNF-alpha, NGF, or EPO did not substitute for MEA in our standard proliferation assay.
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PMID:Thiol-sensitive mast cell lines derived from mouse bone marrow respond to a mast cell growth-enhancing activity different from both IL-3 and IL-4. 278 56

A growth factor acting synergistically with IL-3 on thiol-sensitive "mucosal type" bone marrow-derived mast cell lines, and therefore termed mast cell growth enhancing activity, is present in PWM stimulated spleen cell conditioned medium. Mast cell growth enhancing activity can be partially purified and completely separated from IL-3, IL-4, and IL-5, and for the most part from IL-6 and GM-CSF using strong cation exchange and Procion red affinity chromatography. Mast cell growth enhancing activity binds to Con A-Sepharose and can be digested with trypsin and chymotrypsin. It shows a Mr ranging from 37 to 43 kDa under nonreducing SDS-PAGE and a main isoelectric point ranging from 6.2 to 7.3.
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PMID:Partial purification of a mast cell growth-enhancing activity and its separation from IL-3 and IL-4. 278 57


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