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)

The ability of cyclosporine (CSA) and FK506 to inhibit cytokine production by factor-dependent murine mast cell lines was investigated. The mast cell clone, MC/9, and two mast cell lines, MCIII and MCVI, were stimulated to produce cytokines with phorbol myristate acetate plus the calcium ionophore A23187. The production of cytokines by stimulated mast cells cultured in the presence or absence of drug was monitored by bioassay of culture supernatants for induction of proliferation by factor-dependent cell lines and inhibition of these responses by neutralizing monoclonal antibodies. Both CSA and FK506 inhibited mast cell cytokine production at concentrations comparable to those observed with T cells. However, the degree of inhibition of cytokine production varied among the mast cell lines as well as between different cytokines produced by a given mast cell line. For example, CSA completely inhibited interleukin-2 (IL-2), IL-3, IL-4 and granulocyte-macrophage colony stimulating factor secretion by all three lines, with the exception that IL-2/IL-4 production by MCIII was partially resistant to inhibition by CSA. Similarly, FK506 completely inhibited cytokine production by MC/9, partially inhibited cytokine production by MCIII and had differential effects on IL-3/granulocyte-macrophage colony-stimulating factor and IL-2/IL-4 production by MCVI. Consistent with their ability to selectively inhibit cytokine gene transcription in T cells, neither CSA nor FK506 inhibited factor-dependent proliferation by these mast cell lines. In view of the putative role of cytokines in inflammation and late phase asthmatic reactions, these observations may be of particular significance in development of methods of pharmacologic intervention.
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PMID:Cyclosporine and FK506 inhibition of murine mast cell cytokine production. 137 Nov 58

We have previously demonstrated that cyclosporine (CSA) and FK506 are able to selectively inhibit cytokine production by murine mast cell lines at concentrations comparable to those observed with thymus-derived lymphocytes (T cells). The selectivity of these effects were demonstrated by the failure of CSA and FK506 to inhibit cytokine-induced mast cell proliferation at equivalent or higher concentrations. In this report, we examined the ability of rapamycin (RAP) to inhibit cytokine production and cytokine-induced proliferation by a factor-dependent murine mast cell line and compared its activity to that of the structurally related macrolide FK506. The mast cell clone, MC/9, was stimulated to produce cytokines with phorbol myristate acetate plus the calcium ionophore A23187, or to proliferate in response to exogenous cytokines such as interleukin-3 and interleukin-4, produced by the helper T cell clone D10.G4. RAP did not inhibit cytokine production by MC/9, even at concentrations greater than 1000 nM. FK506 and CSA inhibited cytokine production with IC50 of 0.8 and 16.2 nM, respectively. In contrast to its lack of effect on cytokine production, RAP potently inhibited cytokine-induced proliferation of MC/9 cells with an IC50 of 1.9 nM. Because RAP and FK506 are structurally related and yet have divergent biological effects, we examined the ability of RAP to antagonize inhibitory effects of FK506 on mast cell cytokine production and the ability of FK506 to antagonize inhibitory effects of RAP on cytokine-induced mast cell proliferation. The addition of RAP in molar excess reversed inhibition of mast cell cytokine production mediated by FK506, but not that of CSA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rapamycin and FK506 differentially inhibit mast cell cytokine production and cytokine-induced proliferation and act as reciprocal antagonists. 137 61

The immunosuppressive drugs FK506 and cyclosporin A have an identical spectrum of activities with respect to IgE receptor (Fc epsilon RI)-mediated exocytosis from mast cells and T cell receptor-mediated transcription of IL-2. These findings suggest a common step in receptor-mediated signal transduction leading to exocytosis and transcription and imply that immunosuppressive drugs target specific signal transduction pathways, rather than specific cell types. This hypothesis is supported by studies on the effect of rapamycin on IL-3 dependent proliferation of the rodent mast cell line PT18. Rapamycin inhibits proliferation of PT18 cells, achieving a plateau of 80% inhibition at 1 nM. This inhibition is prevented in a competitive manner by FK506, a structural analogue of rapamycin. Proliferation of rat basophilic leukemia cells and WEHI-3 cells was also inhibited, at doses comparable to those shown previously to inhibit IL-2-dependent proliferation of cytotoxic T lymphocyte line (CTLL) cells. In contrast, proliferation of A-431 cells, a epidermoid cell line, was not affected by rapamycin. DNA histograms indicate that complexes formed between the rapamycin-FK506-binding protein (FKBP) and rapamycin arrest-proliferating PT18 cells in the G0/G1-phase. It is concluded that FKBP-rapamycin complexes may inhibit proliferative signals emanating from IL-3 receptors, resulting in growth arrest of cytokine-dependent, hematopoietic cells.
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PMID:The effect of the immunophilin ligands rapamycin and FK506 on proliferation of mast cells and other hematopoietic cell lines. 138 15

Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism.
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PMID:Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. 171 84

The high-affinity receptor for IgE, Fc epsilon RI, represents the major cell surface structure through which mast cells express immunologically specific secretory function. By contrast, the stem cell factor receptor (SCFR), which is encoded by c-kit, is essential for normal mast cell development. The signaling pathways initiated by the stimulation of mast cells through the Fc epsilon RI, which lacks intrinsic kinase activity, and the SCFR, a member of the receptor tyrosine kinase family, generally have been regarded to be distinct. We report here that mouse mast cells stimulated either with SCF or with IgE and specific antigen exhibit a remarkably similar pattern of activation of mitogen-activated protein kinases (MAPK), 90 kDa-S6 kinases (pp90rsk), and pp70-S6 kinases (pp70-S6K). These results indicate that all three families of protein kinases are associated with the cell surface receptor-dependent activation of secretion, as well as proliferation, in mast cells. We also show that the immunosuppressant rapamycin, but not FK506, can inhibit both SCF-dependent pp70-S6 kinase activation and SCF-dependent proliferation in mouse mast cells, without suppressing IgE- and antigen-dependent mediator release. These findings suggest that the activation of pp70-S6 kinase represents an important link in the stimulation of cell proliferation by SCF. Our results also indicate that the intracellular signaling pathways initiated by stimulation of mast cells through the Fc epsilon RI or the SCFR exhibit more overlap than has previously been appreciated.
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PMID:Activation of MAP kinases, pp90rsk and pp70-S6 kinases in mouse mast cells by signaling through the c-kit receptor tyrosine kinase or Fc epsilon RI: rapamycin inhibits activation of pp70-S6 kinase and proliferation in mouse mast cells. 750 92

FK506 and cyclosporin A (CsA) are immunosuppressive agents that inhibit IL-2 production by activated T cells, but only CsA inhibits IgE activation-induced cytokine transcripts in mouse IL-3-dependent, bone marrow-derived mast cells (BMMC). We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein (FKBP) 12, a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro. In this report, we establish that FKBP12 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation-induced cytokine transcripts in a Kirsten murine sarcoma virus-immortalized mast cell line that is FKBP12 deficient. Overexpression of FKBP12 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity (IC50 = 2 nM), compared with cells transfected with the expression vector alone (IC50 > 30 nM). The IC50 value for FK506 inhibition of IgE activation-induced transcripts for TNF-alpha decreased from 40 nM in vector control cells to 10 nM in FKBP12 transfectants. Similarly, the IC50 value for inhibition of IL-6 transcripts decreased from > 1000 nM in vector control cells to 35 nM in FKBP12 transfectants. In contrast, activation-elicited release of the secretory granule mediator beta-hexosaminidase was only partially inhibited by FK506 at 1000 nM, regardless of the levels of FKBP12 expressed by the cells. Thus, FKBP12 is the dominant cytosolic protein that mediates FK506 inhibition of TNF-alpha and IL-6 transcripts.
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PMID:The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells. 753 Jul 43

The immunosuppressive drugs FK506 and rapamycin bind to a family of intracellular proteins termed FK506-binding proteins (FKBP). FK506 and rapamycin inhibit lymphocyte-activation pathways by forming complexes with an FKBP; subsequently, the drug/FKBP complexes interact with target molecules involved in signal transduction. A key target of FK506/FKBP12 complexes is calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. In mammalian cells, rapamycin treatment is associated with inhibition of the activity of several cellular serine/threonine kinases, including p70 S6 kinase. These kinases may function in signaling pathways involving TOR gene producs, which have been shown to interact with rapamycin/FKBP12 complexes in vitro. To determine if FKBP12 mediates the effects of both FK506 and rapamycin in mammalian cells, we overexpressed FKBP12 in a murine mast cell line. Increased expression of FKBP12 resulted in increased sensitivity to FK506 and rapamycin, as measured by inhibition of calcineurin activity and p70 S6 kinase activity, respectively. In contrast, overexpression of FKBP25 had no effect on sensitivity to either drug. Two distinct point mutations in FKBP12, one altering a hydrophobic residue within the drug-binding pocket and the other changing a charged surface residue of FKBP12, abrogated its ability to mediate sensitivity to FK506 and rapamycin. These results establish that FKBP12 can mediate sensitivity to both FK506 and rapamycin in mammalian cells.
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PMID:FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells. 753 90

The immunophilins of the FK506-binding protein (FKBP) family are intracellular proteins that bind the immunosuppresants FK506 and rapamycin. In this study we show that HMC-1 mast cells sensitized with IgE release FKBP12 upon stimulation with anti-IgE. The release is rapid and not affected by actinomycin D or cycloheximide, suggesting that it is due to exocytosis from a storage compartment. FKBP12 from HMC-1 mast cells exhibits biological activity. When applied extracellularly to human neutrophils, it induces transient changes in the intracellular Ca2+ concentration ([Ca2+]i) due to Ca2+ release from intracellular stores. Inhibition of [Ca2+]i changes by ruthenium red and ryanodine indicates that ryanodine receptor/Ca2+ release channels are involved in FKBP12-induced Ca2+ signaling. Neutrophil activation by mast cell-derived FKBP12 is prevented by complexing FKBP12 with FK506 or rapamycin. These results demonstrate that extracellular FKBP12 functions as a cytokine in cell-to-cell communication. They further suggest a pathophysiological role for FKBP12 as a mediator in immediate or type I hypersensitivity and may have implications for novel therapeutic strategies in the treatment of allergic disorders with FK506 and rapamycin.
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PMID:Activation of Ca2+ signaling in neutrophils by the mast cell-released immunophilin FKBP12. 753 32

Hapten-specific and mast cell-dependent biphasic cutaneous reactions were induced by intravenous application of anti DNP-IgE antibodies and a subsequent skin test. These reactions were also demonstrated in SCID mice, which indicates that T cell-mediated immunity might not be involved in these IgE-mediated cutaneous reactions. Simultaneous application of anti histaminics did not suppress these reactions significantly, while several immunomodulators, such as azelastine, FK506, and prednisolone, significantly inhibited both early and late phase reactions except for the failure of FK506 to inhibit the early reaction. Anti-VCAM-1 antibody and anti-tumor necrosis factor-alpha (TNF alpha) antibody but not anti-IL 5 antibody showed similar suppressive effects on both early and late phase reactions. Mast cell and inflammatory cells other than T cells are thought to play an important role in these IgE-induced biphasic reactions. TNF alpha and/or VCAM-1 are required for tissue accumulation of inflammatory cells in this system.
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PMID:Effect of mast cell modulators on IgE-mediated murine biphasic cutaneous reactions. 863 25

Using mouse peritoneal cavity mast cells, we investigated the effects of FK506 and cyclosporin A (CsA) on cell proliferation and histamine release induced by anti-IgE antibody, calcium ionophore (A23 187), or neuropeptide (substance P). Both FK506 and CsA inhibited cytokine-dependent mast cell proliferation in a dose-dependent manner. The inhibitory effects of these compounds on mast cell proliferation was reversible; the removal of the chemicals from the incubation medium resulted in the reinitiation of mast cell proliferation. Flow cytometric analysis suggested that the inhibitory effect of FK506 and CsA was mostly due to G1/S boundary block, although a significant number of G2-arrested cells were also observed following FK506 treatment. Both FK506- and CsA-treated mast cells showed a similar inhibition of histamine release induced by A23187. However, CsA at higher concentrations inhibited the histamine release induced by anti-IgE antibody or substance P more markedly than FK506. Cellular histamine content was decreased by CsA treatment while FK506 had no effect. The staining properties of peritoneal mast cells changed from connective tissue-type mast cell-like to mucosal mast cell-like during CsA treatment but not during FK506 treatment. Thus FK506 and CsA have different effects on mast cell proliferation as well as histamine release, that might be associated with a phenotypic change of the cells during culture.
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PMID:Effects of FK506 and cyclosporin A on proliferation, histamine release and phenotype of murine mast cells. 884 28


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