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)

Stem cell factor (SCF) and interleukin-3 (IL-3) both act on several target hematopoietic populations, including mast cells. We have isolated a unique murine mast cell line, B6M, that is phenotypically similar to immature mast cells. For B6M cells, IL-3 is a survival factor and alone does not stimulate proliferation. SCF can stimulate proliferation of B6M cells, and together IL-3 and SCF synergize to stimulate optimal proliferation and long-term growth. A sustained induction of c-myc is observed only in the presence of SCF (with or without IL-3). In B6M cells, both IL-3 and SCF stimulate phosphorylation of Shc and activation of the Ras, Raf-1, MAPK pathway. Interestingly, IL-3 plus SCF synergistically activate MAPK. IL-3, but not SCF, leads to activation of Jak 2 and Stat 5 and induces pim-1 expression. From these data, we suggest that the induction of pim-1 and c-myc is independently regulated. Furthermore, IL-3-stimulated activation of the Jak 2/Stat 5 pathway, induction of pim-1, and activation of the Ras/MAPK pathway are insufficient to mediate proliferation of B6M cells. The unusual IL-3 response of B6M cells provides a useful model to dissect signals required for IL-3-stimulated survival and proliferation.
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PMID:Signaling pathways activated in a unique mast cell line where interleukin-3 supports survival and stem cell factor is required for a proliferative response. 861 90

Bruton's tyrosine kinase (Btk) plays crucial roles in B cell differentiation as well as mast cell activation through the high-affinity IgE receptor (FcepsilonRI). Defects in the btk gene lead to agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Mast cells from xid and btk null mice exhibit mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FcepsilonRI cross-linking. Recent studies demonstrated the role of Btk in a sustained increase in intracellular calcium concentrations in response to antigen receptor stimulation. Btk is also involved in the activation of stress-activated protein kinases, JNK/SAPK1/2, and thereby regulates c-Jun and other transcription factors that are important in cytokine gene activation. Regulation of the JNK/SAPK activation pathway by Btk may be related to the proapoptotic function of Btk in the programmed cell death in these hematopoietic cells.
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PMID:Functions of Bruton's tyrosine kinase in mast and B cells. 1008 May 29

We studied the involvement of phosphatidylinositol 3-kinase (PI3-kinase) in the antigen-induced IL-4 production in a rat mast cell line, RBL-2H3. The stimulation of IgE-sensitized RBL-2H3 cells by the antigen resulted in increased IL-4 mRNA levels followed by increased IL-4 production. Wortmannin and LY294002, PI3-kinase inhibitors, partially reduced both the antigen-induced increases in the IL-4 mRNA levels and IL-4 production in a concentration-dependent manner. Extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK), which belong to the MAPK family, were activated by the antigen stimulation, and the activation of p38 MAPK in addition to JNK was suppressed markedly by wortmannin. The phosphorylation of endogenous activating transcription factor-2, a substrate of p38 MAPK, was also inhibited by wortmannin. The specific p38 MAPK inhibitor SB203580 partially inhibited the antigen-induced IL-4 production at mRNA levels, but the MEK-1 inhibitor PD98059 enhanced it. These findings suggest that the activation of PI3-kinase and p38 MAPK is partially responsible for the antigen-induced IL-4 production in RBL-2H3 cells.
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PMID:Involvement of a phosphatidylinositol 3-kinase-p38 mitogen activated protein kinase pathway in antigen-induced IL-4 production in mast cells. 1061 55

Thapsigargin, which elevates cytosolic calcium levels by inhibiting the sarcoplasmic/endoplasmic reticulum calcium-dependent ATPase, was tested for its ability to degranulate bone marrow-derived mast cells (BMMCs) from src homology 2-containing inositol phosphatase +/+ (SHIP+/+) and SHIP-/- mice. As was found previously with steel factor, thapsigargin stimulated far more degranulation in SHIP-/- than in SHIP+/+ BMMCs, and this was blocked with the phosphatidylinositol-3 (PI-3) kinase inhibitors, LY294002 and wortmannin. In contrast to steel factor, however, this heightened degranulation of SHIP-/- BMMCs was not due to a greater calcium influx into these cells, nor was the thapsigargin-induced calcium influx inhibited by LY294002, suggesting that the heightened thapsigargin-induced degranulation of SHIP-/- BMMCs was due to a PI-3 kinase-regulated step distinct from that regulating calcium entry. An investigation of thapsigargin-stimulated pathways in both cell types revealed that MAPK was heavily but equally phosphorylated. Interestingly, the protein kinase C inhibitor, bisindolylmaleimide (compound 3), totally blocked thapsigargin-induced degranulation in both SHIP+/+ and SHIP-/- BMMCs. As well, thapsigargin stimulated a PI-3 kinase-dependent, transient activation of protein kinase B, and this activation was far greater in SHIP-/- than in SHIP+/+ BMMCs. Consistent with this, thapsigargin was found to be a potent survival factor, following cytokine withdrawal, for both cell types and was more potent with SHIP-/- cells. These studies have both identified an additional PI-3 kinase-dependent step within the mast cell degranulation process, possibly involving 3-phosphoinositide-dependent protein kinase-1 and a diacylglycerol-independent protein kinase C isoform, and shown that the tumor-promoting activity of thapsigargin may be due to its activation of protein kinase B and subsequent promotion of cell survival.
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PMID:Thapsigargin-induced degranulation of mast cells is dependent on transient activation of phosphatidylinositol-3 kinase. 1086 Oct 44

Ligation of the high-affinity IgE receptor (FcepsilonRI) or of c-Kit stimulates cytokine production in mast cells. We show that MEK kinase 2 (MEKK2), a MAPK kinase kinase (MAP3K) that regulates the JNK and ERK5 pathways, is required for cytokine production in embryonic stem (ES) cell-derived mast cells (ESMC). Targeted disruption of the MEKK2 or MEKK1 gene was used to abolish expression of the respective kinases in ESMC. Transcription of specific cytokines in response to IgE or c-Kit ligand was markedly reduced in MEKK2(-/-) ESMC relative to wild-type ESMC. Cytokine production in MEKK1(-/-) ESMC was similar to that of wild-type ESMC, demonstrating the specificity of MEKK2 in signaling cytokine gene regulation. MEKK2(-/-) ESMC also lost receptor-mediated stimulation of JNK. In contrast, JNK activation in response to UV irradiation was normal, showing that MEKK2 is required for receptor signaling but not for cellular stress responses. MEKK2 is the first MAP3K shown to be required for mast cell tyrosine kinase receptor signaling controlling cytokine gene expression.
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PMID:MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. 1103 6

Immunoglobulin E (IgE) is important in mediating human allergic diseases. We tested the hypothesis that a human Ig Fc gamma-Fc epsilon bifunctional chimeric protein, GE2, would inhibit IgE class switch recombination (CSR) by co-aggregating B-cell CD32 and CD23. Indeed, GE2 directly inhibited epsilon germ-line transcription, subsequent CSR to epsilon and IgE protein production. This CSR inhibition was dependent on CD23 binding and the phosphorylation of extracellular signal-related kinase (ERK), and it was mediated via suppression of interleukin-4-induced STAT6 phosphorylation. Treatment with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase 1 (MAPKK1 (MEK1)) and MEK2 reversed the ability of GE2 to decrease CSR and STAT6 phosphorylation. GE2 stimulation induced ERK phosphorylation, whereas it did not alter the phosphorylation of c-Jun N-terminal kinase or p38 MAPK. The ability of GE2 to block human isotype switching to epsilon, in addition to its already demonstrated ability to inhibit mast cell and basophil function, suggests that it will provide an important novel benefit in the treatment of IgE-mediated diseases.
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PMID:Inhibition of interleukin-4-induced class switch recombination by a human immunoglobulin Fc gamma-Fc epsilon chimeric protein. 1280 27

Mast cell accumulation can be causally related to several allergic inflammations. Previous work has demonstrated that glucocorticoids decreased tissue mast cell number, and stem cell factor (SCF)-induced migration of mast cells required p38 MAPK activation. In the present study we investigated the effects of dexamethasone on SCF-induced migration of rat peritoneal mast cells (RPMCs). SCF significantly induced the migration of RPMCs at 4 h. Dexamethasone dose-dependently inhibited SCF-induced migration of RPMCs (approximately 90.1% at 100 nM; P < 0.05). The MAPK p38 inhibitor SB203580 (20 microM) also inhibited the SCF-induced migration. The ability of SCF to enhance morphological alteration and filamentous actin formation was also abolished by treatment with dexamethasone. Dexamethasone inhibited SCF-induced p38 MAPK activation to near-basal levels and induced MAPK phosphatase-1 expression. In addition, SCF-induced inflammatory cytokine production was significantly inhibited by treatment with dexamethasone or SB203580 (P < 0.01). Our results show that dexamethasone potently regulates SCF-induced migration, p38 MAPK activation, and inflammatory cytokine production through the expression of MKP-1 protein in RPMCs. Such modulation may have functional consequences during dexamethasone treatment, especially mast cell-mediated allergic inflammation disorders.
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PMID:Inhibition of the stem cell factor-induced migration of mast cells by dexamethasone. 1293 82

Mitogen-activated protein kinase (MAPK) cascades play essential roles in the transduction of extracellular signals to cytoplasmic and nuclear effectors. The MAPK kinase kinase MEKK2 is essential for activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5). These pathways are important for expression of specific cytokine genes in mast cells following cross-linking of the high-affinity IgE receptor (FcepsilonRI). A consequence of ERK5 activation is activation of the transcriptional factor myocyte enhancing factor-2C (MEF2C), leading to increased c-Jun expression. We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5. Following phosphorylation of MEF2C, activated MEF2C regulates transcription of c-Jun but not TNF-alpha. Inhibition of ERK5, MEK5 activation or activation of MEKK2-deficient mast cells was associated with inhibition of MEF2C phosphorylation and a decrease in c-Jun expression. Thus, these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells following FcepsilonRI cross-linking. These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcepsilonRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.
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PMID:MEF2C regulates c-Jun but not TNF-alpha gene expression in stimulated mast cells. 1451 74

Asthma is a chronic inflammatory disease of the airways. Mast cell-derived cytokines may mediate both airway inflammation and remodeling. It has also been shown that fibroblasts can be the source of proinflammatory cytokines. In the human airways, mast cell-fibroblast interactions may have pivotal effects on modulating inflammation. To study this further, we cocultured normal human lung fibroblasts (NHLF) with a human mast cell line (HMC-1) and assayed for production of interleukin (IL)-6, an important proinflammatory cytokine. When cultured together, NHLF/HMC-1 contact induced IL-6 secretion. Separation of HMC-1 and NHLF cells by a porous membrane inhibited this induction. HMC-1-derived cellular membranes caused an increase in IL-6 production in NHLF. Activation of p38 MAPK was also seen in cocultures by Western blot, whereas IL-6 production in cocultures was significantly inhibited by the p38 inhibitor SB203580. IL-6 production in cocultures was minimally inhibited by a chemical inhibitor of nuclear factor-kappaB (Bay11), indicating that nuclear factor-kappaB may have a minimal role in signaling IL-6 production in mast cell/fibroblasts cocultures. Blockade of inter-cellular adhesion molecule-1, tumor necrosis factor-RI, and surface IL-1beta with neutralizing antibodies failed to significantly decrease IL-6 production in our coculture, indicating that other receptor-ligand associations may be responsible for this activation. These novel studies reveal the importance of cell-cell interactions in the complex milieu of airway inflammation.
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PMID:Human lung fibroblasts express interleukin-6 in response to signaling after mast cell contact. 1456 41

Mast cells are crucial effector cells in the immune response through mediator secretion and release of cytokines. A coordinated balance between protein kinases and phosphatases plays an essential role in the regulation of mast cell mediator secretion. We have previously shown that treatment of mast cells with okadaic acid (OA), a protein phosphatase 2A (PP2A) inhibitor, results in a dose-dependent increase in interleukin (IL)-6 production. We show here for the first time a synergism between OA and immunoglobulin E (IgE)-mediated IL-6 secretion by murine bone marrow-derived mast cells (BMMC). Selective p38 mitogen-activated protein kinase (p38 MAPK) inhibition reduces OA and IgE-mediated IL-6 production. Regulation of p38 MAPK by PP2A was demonstrated, as OA treatment caused a dose-dependent increase in p38 MAPK phosphorylation. Antigen-mediated activation of murine mast cells also resulted in an increase in p38 MAPK phosphorylation, which was potentiated by cotreatment of the cells with OA. Lastly, in two mast cell lines (human mast cell-1 5C6 and murine MC/9) and primary-cultured murine BMMC, we show by coimmunoprecipitation an interaction between p38 MAPK and PP2A. These data support a role for PP2A through interaction with p38 MAPK in the regulation of IgE-dependent mast cell activation.
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PMID:Phosphatase inhibition potentiates IL-6 production by mast cells in response to FcepsilonRI-mediated activation: involvement of p38 MAPK. 1531 34


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