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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells produce a number of cytokines including IL-6. In view of the large amounts of de novo synthesis induced by the activation of rat peritoneal mast cells and previous observations of expression of this cytokine by human lung mast cells, we have studied the regulation of IL-6 production. We examined the hypothesis that mast cell IL-6 production is not related to previous histamine release. Highly purified rat peritoneal mast cells were activated with anti-IgE, calcium ionophore A23187, or LPS. Histamine was used as a marker of preformed mediator release and IL-6 production was assessed by using the B9 hybridoma growth factor bioassay. Anti-IgE activation of rat peritoneal mast cells induced IL-6 production and histamine release. In contrast, LPS activation induced substantial, serum-dependent, IL-6 production without a significant level of histamine release. No preformed IL-6 was detected in the cells. Calcium ionophore induced histamine release from mast cells to a greater extent than did anti-IgE, but no A23187-induced IL-6 production was observed. A23187-treated cells retained high viability and produced a significant amount of TNF-alpha. To further examine the concordance of IL-6 production and histamine release we used mast cell stabilizing drugs. Dexamethasone and nedocromil significantly inhibited IL-6 production in response to anti-IgE. Our results demonstrate that there is not a direct relationship between mast cell degranulation and IL-6 production. Our observations are important for understanding the role of mast cells in inflammation and for developing strategies to modulate mast cell function in disease.
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PMID:IL-6 production by rat peritoneal mast cells is not necessarily preceded by histamine release and can be induced by bacterial lipopolysaccharide. 751 39

We have previously reported a method of mast cell induction by long-term culture of mouse spleen cells without using exogenous mast cell growth factor (Z.-Q. Hu, T. Yoshida, and T. Shimamura, J. Immunol. Methods 149:173, 1992). Supernatants recovered from the long-term cultures contain endogenous interleukin 3 and soluble stem cell factor. These were assessed by the capacity of the recovered supernatants to foster the growth of a mast cell growth factor-dependent cell line and by neutralizing antibodies. Besides the soluble factors, cell-to-cell contacts mediated by membrane stem cell factor on splenic stromal cells and c-Kit receptors on mast cells also affect mast cell induction. Different lots of fetal calf serum (FCS) were examined to determine a possible trigger for cytokine production. FCS can be divided into mast cell-inducible and noninducible sera by this process. However, not all FCS lots contain mast cell growth factor. The mast cell-inducible lots contain lipopolysaccharide (LPS) confirmed by a Limulus assay. Polymyxin B can neutralize the mast cell induction activity. Non-mast cell-inducible FCS can be converted to inducible FCS by adding exogenous LPS. The results indicate that LPS as a trigger of cytokine production is responsible for mast cell induction.
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PMID:Effect of lipopolysaccharide on mouse mast cell induction by a splenic cell culture system. 752 Apr 22

Mouse bone marrow (BM) was cultured in the presence of recombinant mouse (rm) interleukin-3 (IL-3), rmIL-4, rmIL-5, rmIL-7, purified mouse (m) IL-9, rmIL-10, recombinant human (rh) macrophage-colony-stimulating factors (M-CSF), rm granulocyte-macrophage colony-stimulating factors (GM-CSF) rm stem cell factor (SCF), rh interferon-alpha (IFN-alpha), rmIFN-gamma, and mNGF to determine which cytokine would give rise to mast cells in murine BM cultures. From a starting population of 1 x 10(7) cells, 1.55 x 10(7) mast cells developed within 14 days in cultures supplemented by rmIL-3. No mast cells were seen at day 14 when any of the other cytokines were present alone, except for rmSCF, which supported the growth of < 0.01% of mast cells observed in IL-3-dependent BM cultures. When rmIL-4, -5, -7, -10, mIL-9, rhM-CSF, rmGM-CSF, rmSCF, rhIFN-alpha, -gamma, or mNGF were added to BM cultures in the presence of rmIL-3, mast cell growth increased 200% with the addition of rmSCF, and 10% when rmIL-4 or IL-9 was added. However, the addition of rhM-CSF, rmGM-CSF, rmIFN-gamma, and mNGF decreased the number of mast cells. Mast cell number, as determined by metachromatic stains, generally approximated the number of Fc epsilon RI+ cells as assessed by FACS analysis. Among the cytokines, only rmIL-4 and rmSCF were able to support the survival of mast cell progenitors in the absence of obvious mast cell proliferation, similarly to rmIL-3. Only rmSCF alone, or in combination with rmIL-3 or -4, supported the growth of mast cells from mouse peripheral blood mononuclear cells (PBMC) where the number of mast cell precursors was about 90 per 10(6) PBMC. With time, mouse BM cells cultured in rmIL-3 became more responsive to rmSCF. Taken together, these data demonstrate that IL-3 is a major early mast cell growth factor, that mast cells become more dependent on SCF with time, and that the effects of IL-3 and SCF are upregulated (IL-4) or downregulated (M-CSF, GM-CSF, IFN-gamma) by both growth factors and proinflammatory cytokines.
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PMID:Demonstration of differential effects of cytokines on mast cells derived from murine bone marrow and peripheral blood mononuclear cells. 752 67

To obtain further information regarding the role of cytokines during mast cell differentiation, we have investigated changes of cytokine secretion in mast cells developing from the human peripheral blood monocytic cell fraction during culture with fibroblast-derived conditioned media. The influence of stem cell factor and an antibody to the respective receptor in our culture system was studied as well. Interleukin (IL)-1 alpha, IL-1 beta, IL-6, and tumor necrosis factor (TNF)alpha were spontaneously secreted by cultured cells at day 1 and decreased markedly by day 14. Similar changes occurred also during culture with stem cell factor and were partially abrogated by an anti-receptor antibody. IL-8 was secreted at a high level throughout the culture, whereas no spontaneous secretion of IL-2, IL-3, IL-4, and IL-7 was measured at all. Upon stimulation with phorbol myristate acetate and A23187, cultured cells showed substantially more release of IL-3 and TNF-alpha after 14 d of culture, compared to peripheral blood monocytic cells. Preformed TNF-alpha was found in one of three monocytic cell preparations from peripheral blood, but not in monocytic cell-derived mast cells. During mast cell differentiation, cytokines from monocytic cells are therefore downregulated while the cells assume a pattern typically found in mast cells.
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PMID:Comparative cytokine release from human monocytes, monocyte-derived immature mast cells, and a human mast cell line (HMC-1). 752 30

Interleukin 3 (IL-3) induces proliferation and differentiation of mast cell progenitors in vitro, whereas it induces granulocytosis in vivo. In this paper, a positive feedback mechanism of granulopoiesis was studied in order to elucidate the granulocytosis induced by IL-3 in mouse. IL-3 induced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in total bone marrow cells and a marrow adherent cell population. In fractionated marrow cell populations, a different expression pattern of induction of IL-3 stimulation was observed; GM-CSF was expressed in macrophages and fraction 1 (P < 1.061) and 2(1.061 < P 1.074) of bone marrow cells fractionated by equilibrium density centrifugation, G-CSF was expressed in macrophages and fraction 2 and 3 (1.074 < P < 1.097), and interleukin 6 (IL-6) in macrophages and fraction 1 to 3. These results indicate a hierarchical regulation of cytokine production and the existence of a positive feedback mechanism in granulopoiesis. IL-6, induced by IL-3, stimulates stem cells into cycle and induces stem cells to respond to IL-3. The stem cells differentiate to granulocyte-macrophage colony-forming cells by the combined effect of IL-3 and IL-6. IL-3 also induces GM- and G-CSF expression which in turn makes granulocyte-macrophage colony-forming cells differentiate to granulocytes. These factors organize a cytokine network in granulopoiesis.
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PMID:Induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in bone marrow and fractionated marrow cell populations by interleukin 3 (IL-3): IL-3-mediated positive feedback mechanisms of granulopoiesis. 753 Apr 67

It has previously been shown that mouse bone marrow-derived mast cells (BMMC) synthesize and secrete endothelin-1 (ET-1) and express ETA-type endothelin receptors (ETA-R). The study presented here was designed to elucidate the influence of different cytokine conditions for cellular differentiation and maturation on the ability of primary mouse BMMC to respond to exogenous ET-1. BMMC were grown for 2 wk in IL-3 alone and then cultured for 2 to 3 wk with kit ligand (KL) and/or IL-3 in the presence or absence of IL-4. ET-1 induced a very rapid (< or = 1 min) and dose-dependent release of histamine and serotonin from BMMC cultured in the presence of both IL-3 and IL-4. The effect of ET-1 was quantitatively comparable with IgE/Ag-induced mediator release and comprised up to 20% and 16% of total cellular histamine and serotonin, respectively. In BMMC grown with KL or KL plus IL-3, a substantial effect of ET-1 on amine release was only observed when IL-4 had been included in the culture medium. These IL-4 effects could not be observed if BMMC grown in IL-3 and/or KL were preincubated for 1 or 24 h with IL-4 before activation with ET-1, suggesting that a differentiation process rather than a functional priming effect had been initiated by IL-4. In BMMC, the histamine and serotonin release induced by ET-1 (10(-6) M) was inhibited by an ETA-R-specific antagonist (cyclic [D-Asp-Pro-D-Val-Leu-D-Trp]) in a dose-dependent manner, with complete inhibition at an antagonist concentration of 10(-8) M. ET-1 stimulated leukotriene C4 biosynthesis up to 4.5-fold in BMMC cultured in the presence of IL-4. No such ET-1 effect was observed in BMMC cultured in media containing IL-3, KL, or a combination of both cytokines. Peritoneal cells (containing 2 to 3% serosal mast cells) obtained from BALB/c mice released 87 +/- 2% of histamine within 1 min after challenge with ET-1. Our results demonstrate that ET-1 can directly act as a histamine and serotonin secretagogue and as a stimulator of leukotriene C4 production in mast cells. IL-4 appears to be critically involved in the differentiation of immature mast cell precursors to an ET-1-reactive phenotype.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:IL-4 renders mast cells functionally responsive to endothelin-1. 753 Jul 42

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

In mast cells, antigen-mediated aggregation of the high-affinity receptor for immunoglobulin E, Fc epsilon RI, stimulates tyrosine phosphorylation and activation of multiple signaling pathways leading to the release of several classes of mediators of the allergic response. Early events induced upon cross-linking of Fc epsilon RI include tyrosine phosphorylation of Fc epsilon RI subunits and activation of the tyrosine kinase p72syk (Syk), which binds to tyrosine-phosphorylated Fc epsilon RI. Clustering of Syk, as a result of its interaction with aggregated Fc epsilon RI, may play a role in activating one or more of the signaling pathways leading to mediator release. To test this possibility, Syk was introduced into a model mast cell line (rat basophilic leukemia cells) as part of a chimeric transmembrane protein containing the extracellular and transmembrane domains of CD16 and CD7, respectively. Clustering of the Syk chimera, using antibodies against CD16, was found to be sufficient to stimulate early and late events normally induced by clustering of Fc epsilon RI. Specifically, aggregation of Syk induced degranulation, leukotriene synthesis, and expression of cytokine genes. Induction of mediator release was dependent on the kinase activity of Syk. Consistent with this finding, clustering of Syk also induced the tyrosine phosphorylation of a profile of proteins, including phospholipase C-gamma 1 and mitogen-activated protein kinase, similar to that induced upon clustering of Fc epsilon RI. These results strongly suggest that Syk is an early and critical mediator of multiple signaling pathways that emanate from the Fc epsilon RI receptor and give rise to the allergic response.
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PMID:Clustering of Syk is sufficient to induce tyrosine phosphorylation and release of allergic mediators from rat basophilic leukemia cells. 753 80

When mast cells are activated through their immunoglobulin (Ig)E receptors, release of low molecular weight mediators like histamine is followed by secretion of multiple cytokines, including interleukin (IL)-3, IL-4, IL-5, and granulocyte/macrophage colony-stimulating factor. Here we report that stimulated mast cells also synthesize IL-13 mRNA and protein; secretion of this cytokine may be of particular importance because of its ability to stimulate IgE expression. IL-13 transcripts detected by a semiquantitative reverse transcriptase-mediated polymerase chain reaction assay were induced within 30 min after stimulation of mast cells by dinitrophenyl plus monoclonal IgE anti-dinitrophenyl, and peaked at about 1 h. Within 3 h of IgE stimulation, secreted IL-13 bioactivity, estimated by proliferation of an IL-13-dependent cell line, reached levels equivalent to 1-2 ng/ml of IL-13. When added to human B lymphocytes, the mast cell-derived IL-13 activity (like bone fide IL-13) induced Ig C epsilon transcripts, DNA recombination characteristic of the isotype switch to C epsilon, and the secretion of IgE protein. These results suggest a model of local positive feedback interactions between mast cells and B cells, which could play a role in the pathogenesis of atopy.
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PMID:Activated mast cells produce interleukin 13. 753 36

Mast cells are traditionally associated with an acute response involving the short-term release of mediators such as histamine. We have shown previously that mast cells can produce IL-6 without prior histamine release. In this study we examined the hypothesis that mast cell IL-6 production can be selectively regulated by PGs. Highly purified rat peritoneal mast cells were cultured in the presence of PGE1, PGE2, or PGD2 alone or in combination with anti-IgE or bacterial LPS. Histamine release was assessed after 10 min; IL-6 and TNF-alpha production was measured in supernatants after 18 h. Mast cell IL-6 production was induced by PGE1 and PGE2 to a similar level to that observed in anti-IgE-activated cells. In contrast, constitutive production of TNF-alpha was inhibited by PGE1 and PGE2, but not by PGD2. PGE2 had a synergistic effect, inducing IL-6 in the presence of LPS, whereas an additive effect was observed in the presence of anti-IgE. None of the prostanoids alone induced significant histamine release at the 10-min time point. However, PGE2 significantly increased histamine release when added concurrently with anti-IgE. Flurbiprofen in the context of anti-IgE or LPS activation did not alter mast cell IL-6 or TNF-alpha production. IL-6 production in response to each of the stimuli was significantly inhibited by the corticosteroid dexamethasone. These observations of selective modulation of mast cell cytokine production are important to understand the mechanisms by which mast cells interact with other cells during an inflammatory process involving prostanoid synthesis.
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PMID:Prostanoid enhancement of interleukin-6 production by rat peritoneal mast cells. 753 79


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