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)

We report a case of a patient with systemic mastocytosis who was treated with interferon-gamma. Because of severe diarrhoea, nausea and weight loss due to mast cell infiltration of the gastric mucosa the patient received 150 micrograms d-1 interferon-gamma subcutaneously for 10 months. During therapy, the plasma concentrations of IL-3, IL-4 and GM-CSF, which seem to play a role in mast cell growth and differentiation were monitored. The patient had good symptomatic relief and the initially very high eosinophil counts in the peripheral blood showed a partial reduction. However, after 4 months of therapy the patient relapsed. In serum obtained after the relapse, but not in stored serum from the beginning of the therapy, neutralizing antibodies against interferon-gamma were found. Therefore an initial response to the therapy and a secondary failure mediated by treatment-induced antibodies against recombinant interferon-gamma might be suggested. Interferon-gamma may be a well tolerated therapeutic option in systemic mastocytosis. However, treatment-induced neutralizing antibodies against recombinant interferon-gamma should be considered if secondary treatment failure occurs.
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PMID:Treatment of systemic mastocytosis with interferon-gamma: failure after appearance of anti-IFN-gamma antibodies. 758 19

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 ability of subcutaneously (s.c.) injected cytokines (IL-4, IL-5, IL-6, IFN alpha, IFN gamma, GMCSF) to regulate the induction of hapten-specific immediate hypersensitivity (IH) responses was studied in BPO-KLH (benzylpenicilloyl-keyhole limpet hemocyanin) sensitized BALB/c mice at the peak of a hapten-specific IgE antibody forming cell (AFC) response. To induce IH responses, mice were injected in the right pinna with either BPO-BSA (benzylpenicilloyl-bovine serum albumin), BPO-KLH (0.01-1.0 micrograms/ml) or mcAb anti-IgE (0.001 - 1.0 micrograms/ml); and in the left pinna with an equal volume of saline (0.05 ml). Pinnae were measured 5 min to 4 hr later using a micrometer caliper. Treatment of mice with IL-4 or IFN gamma dramatically suppressed the induction of IH responses in dose dependent fashion. In contrast, treatment of mice with IL-6 and IFN alpha increased these responses in dose dependent fashion, while GMCSF and IL-5 had no effect. The suppression obtained with IL-4 and IFN gamma, and the increases seen with IL-6 and IFN alpha, were transient since these cytokines, as well as GMCSF and IL-5, had no effect on IH responses elicited 21 days after the peak of BPO-specific IgE AFC responses. The data suggest that cytokine mediated effects on IH responses occur via changes in serum levels of BPO-specific IgG1 or IgE, through direct or indirect effects of cytokines on mast cells or other cell types, or by affecting the ability of BPO-specific homocytotropic antibodies to bind to mast cell surfaces.
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PMID:Cytokine-induced suppression and potentiation of hapten-specific immediate hypersensitivity responses. 768 21

We recently showed that bone marrow-derived mast cells bore MHC class II molecules and could present antigens to specific T cell hybridomas. This article summarizes the effects of purified recombinant cytokines on the expression of MHC class II molecules by mast cells and on their antigen-presenting capacity. Since IL-3 is essential for mast cell growth, all the cytokines were analyzed in the presence of IL-3. IL-3 downregulated the production of Ia molecules, so that mast cells cultured in IL-3 alone had no antigen presenting ability. In contrast, IL-4 and IFN-gamma upregulated the production of MHC class II molecules, while GM-CSF had no effect. The antigen-presenting capacity of IL-4-treated mast cells was substantially enhanced by incubating these cells with GM-CSF for 2 days. GM-CSF enhanced antigen presentation only in combination with IL-4. The activation of mast cells was reversible and could not be repeated. Finally, incubation of IL-4- or IL-4/GM-CSF-treated mast cells with IFN-gamma led to almost complete inhibition of the antigen-presenting function. These findings provide new insights into the regulation of specific allergic responses.
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PMID:Presentation of soluble antigens by mast cells: upregulation by interleukin-4 and granulocyte/macrophage colony-stimulating factor and downregulation by interferon-gamma. 775 29

The IL-3 receptor (IL-3R) is composed of alpha and beta subunits. Two homologous beta subunits of IL-3R are present in the mouse: AIC2A is the IL-3 specific beta subunit, and AIC2B is the common beta subunit shared by IL-3, IL-5 and granulocyte macrophage colony stimulating (GM-CSF) factor receptors. Both beta subunits form functionally indistinguishable high-affinity IL-3Rs with the same IL-3R specific alpha subunit (IL-3R alpha or SUT-1). Cell surface expression of the alpha and beta subunits of IL-3R was found to be diminished in an IL-3 non-responsive variant (MC/9.IL-4) derived from an IL-3-dependent mast cell line, MC/9. This IL-3R-defective phenotype was dominant based on cell fusion experiments. Moreover, regulatory mechanisms of the alpha and beta subunits are distinct since cell hybrids between MC/9.IL-4 and a CTLL-2 transfectant (CTLL/AS) expressing AIC2A and IL-3R alpha showed a significantly reduced expression of the AIC2A mRNA, while the IL-3R alpha expression was unchanged. Since transcription of both AIC2A and IL-3R alpha cDNAs in the CTLL/AS was driven by an artificial promoter, SR alpha, and nuclear run-off assays showed similar transcriptional rates of the AIC2A gene in both CTLL/AS and the cell hybrids between MC/9.IL-4 and CTLL/AS, the dominant suppression of the beta subunits is post-transcriptional and sequence-specific. A target sequence of the negative regulator must be present within 2756 bases of AIC2A mRNA, which is transcribed from the transfected cDNA in CTLL/AS cells. Similar dominant suppression of the beta subunit expression was also found in a B cell line WEHI231. As the negative regulator suppresses expression of the beta subunits of IL-3, IL-5 and GM-CSF receptors, it has the potential to eliminate all three high-affinity receptors simultaneously.
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PMID:Regulation of IL-3 receptor expression: evidence for a post-transcriptional mechanism that dominantly suppresses the expression of beta subunits. 782 43

The molecular basis for the commitment of multipotential myeloid progenitors to the eosinophil lineage, and the transcriptional mechanisms by which eosinophil-specific genes are subsequently expressed and regulated during eosinophil development are currently unknown. Interleukin-5 (IL-5) is a T cell and mast cell-derived cytokine with actions restricted to the eosinophil and closely related basophil lineages in humans. The high affinity receptor for IL-5 (IL-5R) is composed of an alpha subunit (IL-5R alpha) expressed by the eosinophil lineage, that associates with a beta c subunit shared with the receptors for IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF). As a prerequisite to studies of the transcriptional regulation of the IL-5R alpha subunit gene, we used three different methods, including primer extension, RNase protection, and 5'-RACE to precisely map the transcriptional start site to a position 15 base pairs (bp) upstream of the 5' end of the published sequence of IL-5R alpha exon 1. To initially identify the IL-5R alpha promoter, 3.5 kilobases (kb) and 561 bp of the 5' sequence flanking the transcriptional start site were subcloned into the promoterless pXP2-luciferase vector. Transient transfection of these constructs into an eosinophil-committed HL-60 subline, clone HL-60-C15, induced the expression of approximately 240-fold greater luciferase activity than the promoterless vector, identifying a strong functionally active promoter region within the 561 bp of sequence proximal to the transcriptional start site and with activity equivalent to pXP2 constructs containing the entire 3.5 kb of upstream sequence. To more precisely localize the cis-acting regulatory elements in this region important for promoter activity, a series of 5' deletion mutants of the 561-bp region were generated in the pXP2-luciferase vector. Deletion of the region between bp -432 and -398 reduced promoter activity by more than 80% in the HL-60-C15 cell line. Further analyses of the activity of the IL-5R alpha promoter constructs in various other eosinophil, myeloid, and non-myeloid cell lines indicated that the promoter was relatively myeloid and eosinophil lineage-specific in its expression. Consensus sequences for known transcription factor binding sites were not present in the 34-bp region of the promoter required for maximal activity, suggesting unique myeloid- and possibly eosinophil-specific regulatory elements.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification and characterization of a functional promoter region in the human eosinophil IL-5 receptor alpha subunit gene. 783 16

While LCF is present in BAL early after antigen challenge, we know little about its other potential effects beyond CD4+ T cell, monocyte, and eosinophil chemotaxis and monocyte and CD4+ T cell activation. The work described here focuses on the hypothesis that the secreted protein products of T cells participate in the airway inflammatory process that underlies human asthma, and in particular that LCF could play an early role because of the unusual responsiveness of LCF-producing T to histamine. To date, most studies have addressed the measurement of cytokines derived from CD4+ T cells (e.g., IL-2, IL-3, IL-4, IL-5, and GM-CSF) in the airways of asthmatics, and attempted to correlate the presence of protein or mRNA with the complexion of the inflammatory infiltrate. These studies have been based upon the reports that there are increased numbers of CD4+ T cells in the airways of asthmatics, and that the presence of eosinophils might correlate with the secretion of TH2-type cytokines like IL-3, -4, and -5. Using this information as a background, our work has approached the problem in an entirely different way. We have focused our attention on the early events in antigen-induced asthma that are responsible for CD4+ cell accumulation in the lung, including CD4+ T cells, eosinophils, and monocytes. We have attempted to identify mechanisms by which mast cell mediators, in particular histamine, might play a role in the secretion of chemotactic lymphokines that are selective for CD4+ cells by using CD4 itself as a chemotactic factor receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokine binding to CD4+ inflammatory cells: implications for asthma. 795 94

The supernatant (CM) of long-term bone marrow culture (LTBMC) contains colony promoting activity (CPA) which does not have granulocyte-macrophage (GM) colony-stimulating activity but which enhances GM-colony formation in the presence of CSF. CPA is different from IL-1, IL-3 and GM, G-, and M-CSF. Since CPA-containing LTBMC-CM always contains a substantial level of IL-6, CPA was thought to be similar to IL-6. In the present study, we found that LTBMC with a particular batch of horse serum produced IL-6 without a corresponding production of CPA. Addition of IL-6 to GM-colony assay system in the presence of GM-CSF did not enhance the colony formation. LTBMC-CM did not stimulate proliferation nor differentiation of mast cell progenitors. Anti-IL-6 antibodies suppressed IL-6 activity, but not CPA. These results indicate that CPA is a novel factor distinct from IL-1, IL-3, G-, M-, GM-CSF, IL-6 and SCF (c-kit ligand).
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PMID:Colony promoting activity (CPA) is a novel factor distinct from IL-6. 821 51

The basic helix-loop-helix (bHLH) transcription factors form heterodimers and control steps in cellular differentiation. We have studied four bHLH transcription factors, SCL, lyl-1, E12/E47, and ld-1, in individual lineage-defined progenitors and hematopoietic growth factor-dependent cell lines, evaluating mRNA expression and the effects of growth factors and cell cycle phase on this expression. Single lineage-defined progenitors selected from early murine colony starts and grown under permissive conditions were analyzed by RT-PCR. SCL and E12/E47 were expressed in the vast majority of tri-, bi-, and unilineage progenitors of erythroid, macrophage, megakaryocyte, and neutrophil lineages. Expression for E12/E47 was not seen in unilineage megakaryocyte and erythroid or bilineage neutrophil/mast cell progenitors. Lyl-1 showed a more restricted pattern of expression, although expression was seen in some bi- and unilineage progenitors. No expression was detected in erythroid, erythroid-megakaryocyte-macrophage, macrophage-neutrophil, macrophage, or megakaryocytic progenitors. Id-1, an inhibitory bHLH transcription factor, was also widely expressed in all bi- and unilineage progenitors; only the trilineage erythroid-megakaryocyte-macrophage progenitors failed to show expression. Expression of these factors within a progenitor class was generally heterogeneous, with some progenitors showing expression and some not. This was seen even when two sister cells from the same colony start were analyzed. Id-1, but not E12/E47, mRNA was increased in FDC-P1 and MO7E hematopoietic cell lines after exposure to IL-3 or GM-CSF. Id-1, E12, and lyl-1 showed marked variation at different points in cell cycle in isoleucine-synchronized FDC-P1 cells. These results suggest that SCL, lyl-1, E12/E47, and Id-1 are important in hematopoietic progenitor cell regulation, and that their expression in hematopoietic cells varies in response to cytokines and/or during transit through cell cycle.
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PMID:Expression of basic helix-loop-helix transcription factors in explant hematopoietic progenitors. 876 52

Human mast cells readily release a variety of mediators, including cytokines, in response to IgE receptor crosslinking, but the mechanisms governing the expression of cytokines are still unclear. Using a human mast cell line, HMC-1, we show expression of cytokine transcripts as early as 2 h after activation with ionomycin and phorbol myristate acetate (PMA). Resting HMC-1 cells expressed transcripts for interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, GM-CSF, and weakly for IL-8, and stimulation with ionomycin and PMA induced additional transcripts for IL-6 and IL-13 and upregulated expression of IL-8 transcripts. HMC-1 cells secreted IL-4, IL-8, and GM-CSF protein after activation and dexamethasone significantly inhibited the production of these cytokines. Of significance is the finding that the addition of membranes purified from activated T cells to mast cell cultures induced transcripts selectively for IL-8 and none for other proinflammatory cytokines. Flow cytometry revealed that resting HMC-1 cells express CD40, a molecule involved in contact-dependent signaling of monocytes and B cells by T cells. However, activation of HMC-1 by anti-CD40 antibody did not induce IL-8 gene expression or protein production. This study demonstrates that human mast cells are capable of expressing multiple cytokines that can be inhibited by glucocorticoids. It also raises the possibility that T cells may activate mast cell cytokine synthesis by novel contact-dependent mechanisms. This phenomenon of T cell regulation of mast cell function requires further study.
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PMID:Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids. 908 42


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