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 increase of mast cells at sites of tissue inflammation suggests the production of local factors chemotactic for mast cells. In this report, we demonstrate that the murine mast cell line PT18 and primary mouse bone marrow-derived mast cells chemotax to the basement membrane glycoprotein laminin, and that the synthetic laminin A chain-derived peptide, PA22-2, represents a region of laminin that contains a major chemoattractant site. Mast cell chemotaxis to laminin is enhanced after activation of mast cells by the calcium ionophore, A23187, or PMA and by sensitization of the cells with IgE followed by exposure to antigen. Chemotaxis is not increased in the presence of IL-3 and is independent of mast cell degranulation, as histamine release did not occur when cells were activated with PMA. Mast cell chemotaxis to laminin and its enhancement by IgE-dependent mast cell activation provides a mechanism by which these cells may be attracted to sites of tissue injury. Such activity may be particularly relevant in the response of host tissues to inflammation accompanying parasitic infestations, allergic reactions, and wound healing.
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PMID:Mast cells chemotax to laminin with enhancement after IgE-mediated activation. 259 71

Mast cells clearly are critical for the expression of some IgE-dependent responses, but their roles in other forms of inflammation are uncertain. We previously described a new model system for defining the unique contribution of mast cells to biologic responses in vivo, genetically mast cell-deficient WBB6F1-W/Wv mice that have undergone selective local repair of their mast cell deficiency by the injection of IL-3-dependent cultured mast cells derived from the congenic normal (WBB6F1-+/+) mice. Using this approach, we analyzed the contribution of mast cells to the acute inflammation induced by the epicutaneous application of PMA. Even though PMA can activate a wide variety of cell types that may contribute to acute inflammation, we found that mast cells were required for the full expression of the tissue swelling and leukocyte infiltration associated with the response to the agent in vivo. Thus, in WBB6F1-W/Wv mice selectively reconstituted with dermal mast cells by intradermal injection of cultured WBB6F1-+/+ mast cells into the left ear only, PMA induced approximately twice the tissue swelling and neutrophil infiltration in the mast cell-reconstituted left ears as in the contralateral control ears. This represents the first use of W/Wv mice locally reconstituted with mast cells to confirm the hypothesis that mast cells can represent an important amplification mechanism in acute inflammatory responses of nonimmunologic origin. It also defines a model system that may be generally useful for investigating mast cell-dependent and -independent aspects of acute inflammatory responses.
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PMID:Mast cell-dependent amplification of an immunologically nonspecific inflammatory response. Mast cells are required for the full expression of cutaneous acute inflammation induced by phorbol 12-myristate 13-acetate. 328 Jun 81

Stem cell factor (SCF) or c-kit ligand is a growth factor cytokine produced by stromal cells that is known to influence mast cell proliferation and differentiation. We hypothesized that SCF may also influence the adhesion of mast cells to connective tissue matrix. To examine this hypothesis, we stimulated MCP5/L mast cells or murine bone marrow-derived cultured mast cells (BMCMC) with either SCF or PMA and observed adhesion to fibronectin (FN). As expected, 80 to 90% of PMA-activated MCP5/L cells or BMCMC adhered to FN. In addition, SCF promoted MCP5/L cell or BMCMC adhesion to FN in a dose-response fashion with 50 to 60% of BMCMC adhering to FN at a concentration 10 ng/ml of SCF. BMCMC adhesion was observed with as little as 200 pg/ml of SCF. Adhesion of SCF stimulated BMCMC to FN did not require IL-3, but was dependent on the concentration of FN used to coat the assay surface. Mast cell adhesion in the presence of SCF appeared to occur through an integrin receptor as adhesion was calcium dependent and could be blocked by an RGD (Ang, Gly, Asp)-containing peptide. SCF did not directly mediate adhesion through interaction with c-kit, as FN-coated surfaces exposed to SCF before initiation of the adhesion assay did not promote adhesion in the absence of soluble SCF. Rather, SCF appeared to stimulate adhesion to FN by activating mast cells through its interaction with c-kit. Thus, antibody to SCF blocked adhesion, and rat and murine SCF stimulated BMCMC adhesion to FN, but human SCF, which does not bind to murine c-kit, did not stimulate adhesion. Genistein, which inhibits tyrosine kinase activity, partially inhibited SCF-induced adhesion. SCF thus stimulates mast cell adhesion and, because SCF is produced normally in tissues, it may be a major factor responsible for the adhesion of mast cells to connective tissue matrix under physiologic conditions.
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PMID:Stem cell factor induces mast cell adhesion to fibronectin. 750 10

Demonstration of murine mast cell adhesion to fibronectin (FN) following PMA-mediated cell activation raised the question whether crosslinking of high affinity IgE receptors on mouse mast cells might induce changes in adhesiveness of these cells to FN. Murine mast cells of line MCP5/L were used to investigate the effect of antigenic stimulation on cell adhesion to fN and mediator secretion. effect of antigenic stimulation on cell adhesion to FN and mediator secretion. Adhesion assays were performed using sensitized radiolabeled cells and FN- or BSA-coated 96-well plates. The presence of antigen in the concentrations up to 10 ng/ml resulted in concentration-dependent adhesion potentiation, which was detectable after 5 min, reached maximum at 30 min and persisted or decreased over the next 30 min. Adhesion potentiation decreased at antigen excess and was abolished by heat inactivation of IgE in the antiserum prior to cell treatment. External calcium ion and temperature dependence of adhesion together with the observation that RGD (Arg, Gly, Asp)--containing peptide blocked cell binding to FN suggests that FC epsilon RI crosslinking-induced adhesion potentiation involves an integrin type receptor on cell surface. Sensitized mast cells allowed to adhere spontaneously to FN released more histamine and beta-hexosaminidase upon antigen challenge. Hence, the results show the relations between IgE-induced mast cell activation, adhesion to FN and mediator secretion.
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PMID:Relations between Fc epsilon RI crosslinking-induced mast cell activation and adhesion to fibronectin. 753 25

To identify genes involved in signal transduction pathways that regulate T cell activation and development, murine fetal thymocytes were screened for expression of protein tyrosine kinase family members by the polymerase chain reaction. Using this approach, a non-receptor protein tyrosine kinase, txk, was identified and cloned. Tsk is expressed in thymocytes as early as fetal day 13.5 and its expression at the mRNA level continues throughout development. Txk transcripts are present in thymocytes, peripheral T cells and mast cell lines, but are not detectable in B cell macrophage/monocyte cell lines or in non-hematopoietic fetal or adult tissues. In both thymocytes and T cells, txk transcripts are down-regulated after activation with PMA and ionomycin, concanavalin A or T cell receptor cross-linking. Sequence analysis indicates that txk contains SH2, SH3 and kinase catalytic domains and belongs to the tec family of cytoplasmic protein tyrosine kinases which includes tec, itk and btk. Its unique N-terminus contains a proline-rich region, but unlike the other tec family members, does not contain a pleckstrin homology domain. The restricted expression pattern of txk and its regulation by T cell activation make it an excellent candidate for involvement in signal transduction during thymocyte development.
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PMID:Murine txk: a protein tyrosine kinase gene regulated by T cell activation. 754 61

Adherence of cells to the extracellular matrix via focal adhesions is known to modulate many cellular functions. However, the role of focal adhesions in the regulation of secretion is unclear. To examine this we have used the RBL-2H3 rat mast cell line, in which we and others have observed cytoskeletal rearrangements and increased cell spreading during secretion. All activators of secretion examined, whether acting specifically through or bypassing the IgE-receptor, induced the assembly of focal adhesions, as defined by the localization of vinculin and talin. The extent of focal adhesion formation correlated with the extent of secretion and the time course of secretion also correlated with that of the assembly of focal adhesions. To examine the mechanism by which focal adhesion formation occurred, the protein kinase C inhibitor bisindolylmaleimide was used. Bisindolylmaleimide caused complete inhibition of both secretion and focal adhesion formation induced by antigen or the calcium ionophore A23187. Although PMA did not induce secretion, it induced focal adhesion assembly which was inhibited by bisindolylmaleimide. The inhibitor had no effect on secretion or focal adhesion formation induced by the ATP analogue, ATP gamma S in permeabilized cells, indicating ATP gamma S acts after the activation of protein kinase C in the secretory pathway. These data provide novel evidence that the formation of focal adhesions may have a role in the process of secretion from mast cells.
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PMID:Focal adhesion formation is associated with secretion of allergic mediators. 758 91

There is increasing evidence that the neurologic system is capable of modulating a wide range of immunologic responses, including certain inflammatory processes in the lung, gastrointestinal tract, and skin. It has been proposed that secreted neuropeptides such as substance P (SP) may mediate these neuroinflammatory interactions by binding to and stimulating immune cells such as mast cells and lymphoid cells. SP is secreted in a variety of tissues by an extensive network of neurosensory C and A5 fibers in response to a wide range of noxious stimuli and injury. Previous studies to examine the effect of SP on mast cells have focused on its role in triggering histamine release and mediating immediate hypersensitivity responses. Recently it was demonstrated that mast cells are also capable of secreting multiple cytokines including TNF-alpha, IL-1, IL-3, IL-4, IL-6, and GM-CSF. In this study we tested the possibility that SP may also influence mast cell-mediated late inflammatory events by modulating the production of one or several of these cytokines. Our results indicate that SP induces TNF-alpha mRNA expression and TNF-alpha secretion in a dose-dependent manner in a murine mast cell line, CFTL12. Likewise, SP stimulates TNF-alpha secretion in freshly isolated murine peritoneal mast cells. The induction of mast cell TNF-alpha is selective, since SP does not stimulate the production of IL-1, IL-3, IL-4, IL-6, or GM-CSF in these cells. The CFTL 12 mast cell line constitutively expresses high levels of SP receptor mRNA which is not modulated by PMA/cycloheximide treatment or SP. These results further support the concept that the neurologic system modulates inflammatory events by neuropeptide-mediated mast cell cytokine release.
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PMID:Substance P selectively activates TNF-alpha gene expression in murine mast cells. 768 20

The zinc finger transcription factor GATA-1 is a major regulator of gene expression in erythroid, megakaryocyte, and mast cell lineages. GATA-1 binds to WGATAR consensus motifs in the regulatory regions of virtually all erythroid cell-specific genes. Analyses with cultured cells and cell-free systems have provided strong evidence that GATA-1 is involved in control of globin gene expression during erythroid differentiation. Targeted mutagenesis of the GATA-1 gene in embryonic stem cells has demonstrated its requirement in normal erythroid development. Efficient rescue of the defect requires an intact GATA element in the distal promoter, suggesting autoregulatory control of GATA-1 transcription. To examine whether GATA-1 expression involves additional regulatory factors or is maintained entirely by an autoregulatory loop, we have used a transient heterokaryon system to test the ability of erythroid factors to activate the GATA-1 gene in nonerythroid nuclei. We show here that proerythroblasts and mature erythroid cells contain a diffusible activity (TAG) capable of transcriptional activation of GATA-1 and that this activity decreases during the terminal differentiation of erythroid cells. Nuclei from GATA-1- mutant embryonic stem cells can still be reprogrammed to express their globin genes in erythroid heterokaryons, indicating that de novo induction of GATA-1 is not required for globin gene activation following cell fusion.
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PMID:Positive regulators of the lineage-specific transcription factor GATA-1 in differentiating erythroid cells. 816 66

Expression of a mast cell tryptase mRNA was detected in two human monocytic cell lines, the U-937 and the Mono Mac 6, and in normal human peripheral blood (PB) monocytes. In the U-937 cell line but not in normal PB monocytes, the tryptase expression was upregulated 3-50 fold following phorbol ester (PMA)-induced differentiation, but no such induction was seen after retinoic acid, interferon-gamma or vitamin D3 exposure. The tryptases expressed in PMA-induced and non-induced U-937 and in Mono Mac 6 were characterized by PCR amplification and nucleotide sequence analysis. The U-937 cell line was found to express a tryptase identical to one of the previously cloned mast-cell beta tryptases (Tryptase I), and the tryptase expressed in Mono Mac 6 was found to be nearly identical to the previously cloned alpha tryptase. By northern blot analysis with oligonucleotide probes specific for the alpha and beta tryptases both cell lines were found to express only one type of tryptase. Densitometric quantifications of tryptase mRNA levels, in the two cell lines, showed approximately 80 times higher mRNA levels in Mono Mac 6 compared to non-induced U-937. Immunohistochemical staining for tryptase showed a marked heterogeneity in the Mono Mac 6 cell line. Only one out of 10 cells were positive for the protein but the levels in these cells were very high, equivalent, or even higher than the levels seen in the human mast cell line HMC-1. This shows that the expression of a single tryptase, in this case the alpha tryptase, is sufficient for the production of a stable protein and probably also a stable proteolytically active tetramer. The family of human mast-cell tryptases has been considered to represent a class of proteases specifically expressed in mast cells and basophilic leucocytes. The expression of tryptases in two monocytic cell lines and in normal PB monocytes indicate that in humans, the lineage specificity of these serine proteases is less restricted than earlier expected. The cloning of a full length cDNA for the murine counterpart to the human mast cell tryptases, the MMCP-6, is presented. No expression of the MMCP-6 was detected in a panel of mouse monocyte or macrophage cell lines indicating a species difference in the lineage specificity of the 'mast cell tryptases'.
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PMID:Expression of a mast cell tryptase in the human monocytic cell lines U-937 and Mono Mac 6. 821 Sep 98

IL-4 is a pleiotropic cytokine whose expression is limited to a subset of activated T cells and cells of the basophil/mast cell lineage. It plays a key role in regulating many immune responses; however, little is known about the intracellular signaling events that lead to the selective and transient IL-4 expression in either of these cell types. In this study, the molecular basis of stimulation-dependent transcription in T cells was explored. To identify cis elements that regulate IL-4 gene transcription, various amounts of the 5' flanking region of the murine IL-4 gene were linked to a chloramphenicol acetyl transferase (CAT) reporter gene and tested for the ability to modulate CAT gene transcription in PMA-stimulated EL-4 T cells. These experiments indicate that multiple positive and negative-acting elements contribute to the overall level of IL-4 transcription. These elements are located both proximal and distal to the transcription initiation site (TIS). An activation responsive element is located within 87 bp of the IL-4 gene TIS. This sequence is sufficient to confer responsiveness to PMA-mediated signals and results in a 10- to 20-fold induction of CAT reporter gene activity compared to activity detected in unstimulated cells. Proteins that specifically bind sequences within this region (-88 to -60) are detected in both unstimulated and stimulated EL-4 T cell nuclear extracts. An additional DNA-protein interaction is detected only when extracts from stimulated cells are analyzed. Base substitutions within the -88 to -60 sequence affect both transactivation function and protein/DNA interactions and demonstrate that sequences between -78 and -69 bp are critical. Together, these data support a model in which T cell activation signals stimulate binding of a nuclear protein(s) to a preexisting IL-4 DNA-protein complex. Proteins detected in these promoter proximal DNA-protein complexes are likely to be key elements in facilitating stimulation-dependent IL-4 transcription.
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PMID:An activation-responsive element in the murine IL-4 gene is the site of an inducible DNA-protein interaction. 837 97


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