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 have previously demonstrated that there is a factor present in some human serum which inhibits the passive cutaneous anaphylaxis reaction mediated by IgE. The present study analyzes the effect of this factor on mast cell IgE-dependent tumor necrosis factor (TNF)-alpha release. Rat peritoneal mast cells and RBL-2H3 cells treated with monoclonal mouse IgE anti-dinitrophenol (anti-DNP) followed by DNP-bovine serum albumin (DNP-BSA) were used and TNF-alpha release was measured at different time points. Similarly the percentage of rat peritoneal mast cell degranulation was determined. Results show a period of 30 min as optimal incubation time for TNF-alpha release in both mast cell populations. Human serum anaphylaxis inhibitory factor enriched fraction inhibited TNF-alpha release when it was in contact with IgE before the antigen treatment. Under these conditions the percentage of mast cell degranulation decreased. Mast cells incubated before IgE treatment with the factor alone do not release TNF-alpha and the percentage of degranulation increases due to a non-IgE-dependent process. A possible role of the inhibitory factor in the later phase reaction in addition to immediate hypersensitivity described previously is suggested.
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PMID:Anaphylaxis inhibitory factor in IgE-dependent mast cell stimulation. 1058 2

The SH2-containing protein tyrosine phosphatase1 (SHP-1) is important for signaling from immune receptors. To investigate the role of SHP-1 in mast cells we overexpressed the wild-type and the phosphatase-inactive forms of SHP-1 in rat basophilic leukemia 2H3 (RBL-2H3) mast cell line. The phosphatase-inactive SHP-1 (C453S or D419A) retains its ability to bind tyrosine phosphorylated substrates and thereby competes with the endogenous wild-type enzyme. Overexpression of wild-type SHP-1 decreased the FcepsilonRI aggregation-induced tyrosine phosphorylation of the beta and gamma subunits of the receptor whereas the dominant negative SHP-1 enhanced phosphorylation. There were also similar changes in the tyrosine phosphorylation of Syk. However, receptor-induced histamine release in the cells expressing either wild-type or dominant negative SHP-1 was similar to that in the parental control cells. In contrast, compared with the parental RBL-2H3 cells, FcepsilonRI-induced c-Jun N-terminal kinase phosphorylation and the level of TNF-alpha mRNA was increased in the cells overexpressing wild-type SHP-1 whereas the dominant negative SHP-1 had the opposite effect. The substrate-trapping mutant SHP1/D419A identified pp25 and pp30 as two major potential substrates of SHP-1 in RBL-2H3 cells. Therefore, SHP-1 may play a role in allergy and inflammation by regulating mast cell cytokine production.
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PMID:Positive regulation of c-Jun N-terminal kinase and TNF-alpha production but not histamine release by SHP-1 in RBL-2H3 mast cells. 1064 Jul 70

This study was designed to evaluate the effects of roxithromycin (RXM), a newly synthesized macrolide antibiotic, on cytokine production from mast cells. Mast cells, induced by long-term culture of spleen cells from BALB/c mice, were stimulated with 2.5 micrograms/ml concanavalin A in the presence or absence of various concentrations of RXM. The culture supernatants were obtained 24 h after stimulation. RXM caused a reduction in TNF-alpha levels in culture supernatants in a dose dependent manner and was first detected at a concentration of as little as 0.5 microgram/ml. Metabolized RXM (RU 39001, RU 44981, and RU45179) also suppressed TNF-alpha production in a dose dependent fashion with a minimum concentration of 0.5 microgram/ml. However, metabolized RXM, RU 28111, scarcely affected TNF-alpha production from cultured mast cells. These results strongly suggest that RXM inhibits mast cell function, especially inflammatory cytokine production and may result in favorable modification in inflammatory diseases.
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PMID:Inhibitory action of roxithromycin on tumour necrosis factor-alpha production from mast cells in vitro. 1075 45

This manuscript updates an analysis of the foremost clinical investigation of PHA for aplastic anemias and other disorders associated with impaired hematopoiesis during the years 1963-1967. Humble displayed remarkable insight in motivating the trials long before the recent era during which these disorders have become much better understood. That investigation actually consisted of a series of small pilot studies totaling only 44 patients involving all categories in the aplastic group and 15 miscellaneous disorders mostly neoplastic or premalignant. The most serious of several faults with the studies was the inadequacy of dosages applied, yet much better results were observed than might have been anticipated. Mitogens such as the L4 isolectin of PHA might be applied to treat aplastic anemias in three different ways. (1) For milder direct cytotoxicity types, a stimulating regimen should be applied to increase the production of growth factors and thereby hasten recovery from aplasia. (2) Where hematopoietic stem cell allo-engraftment is needed to replace severely damaged marrow, the mitogen should be included in the preparative regimen. (3) The suppressive protocol of a mitogen that maintains total T cell activation should be added to an established drug regimen such as cyclosporin and antilymphocyte globulin in treating the immuno-mediated aplastic anemias not only to provide superior suppression but to help prevent the late emergence of clonal disorders. The models of L4 isolectin application present advantages not fully offered by any of the other immuno-therapies currently available: broad scope of activities, low morbidity, ease of administration, favorable cost-effectiveness, assurance of reconstituted immune competence, and high potential for cure. However, a more potent mitogen than PHA-L4 not inhibited by serum glycoproteins or immunoglobulins and exhibiting a broader range of modulation would be preferred. A publication by Mann et al. in 1991 suggested that pokeweed mitogen (PWM) showing hundreds of times the potency of PHA-L4 would meet these criteria. Abbreviated reports on two of the studies in the report indicated that PWM had induced lasting remissions of cancers in dogs with nine injections in the mid-range of microgram doses over three weeks. The key study done by Mann himself demonstrated complete disappearance of canine gliomas in a carefully devised humane model applied to five dogs in which the transplantable tumor was established by extradural injection. Also impressive were lasting remissions of autonomous solid neoplasms in four dogs under the care of local veterinarians given PWM supplied by Mann. The critical aspect of these studies, both of which have been extended substantially, is the need keep the dosage within a precisely determined range to avoid loss of efficacy and possibly the occurrence of adverse effects. A review of basic studies now indicates the principle mechanism of response to be binding of PWM with tumor cells that then attract mast cells generated by stem cell factor the production of which is stimulated by the mitogen. Degranulation of mast cell granules releases TNF-alpha and IL-1 at the tumor site with resulting disappearance of neoplastic tissue in the absence of severe systemic effects. For cancer therapy, this represents a highly effective deviation from the stimulation of multiple pathways of immune response usually surmised with mitogens such as PHA-L4. This interpretation illustrates the probability that alternative plant mitogens, each with its unique properties, will likely become available to complement PHA-L4 or displace it from the prime standing as an immunomodulator.
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PMID:PHA for aplastic anemias: the alpha but not the omega of mitogen therapies. 1085 Mar 47

Mature mast cells are generally considered to be less mobile cells residing within tissue sites. However, mast cell numbers are known to increase in the context of inflammation, and mast cells are recognized to be important in regulating local neutrophil infiltration. CXC chemokines may play a critical role in this process. In this study two human mast cell-like lines, HMC-1 and KU812, and human cord blood-derived primary cultured mast cells were employed to examine role of stromal cell-derived factor-1 (SDF-1) in regulating mast cell migration and mediator production. It was demonstrated that human mast cells constitutively express mRNA and protein for CXCR4. Stimulation of human mast cells with SDF-1, the only known ligand for CXCR4, induced a significant increase in intracellular calcium levels. In vitro, SDF-1 alpha mediated dose-dependent migration of human cord blood-derived mast cells and HMC-1 cells across HUVEC monolayers. Although SDF-1 alpha did not induce mast cell degranulation, it selectively stimulated production of the neutrophil chemoattractant IL-8 without affecting TNF-alpha, IL-1beta, IL-6, GM-CSF, IFN-gamma, or RANTES production, providing further evidence of the selective modulation of mast cell function by this chemokine. These findings provide a novel, SDF-1-dependent mechanism for mast cell transendothelial migration and functional regulation, which may have important implications for the local regulation of mast cells in disease.
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PMID:Human mast cells transmigrate through human umbilical vein endothelial monolayers and selectively produce IL-8 in response to stromal cell-derived factor-1 alpha. 1086 Oct 54

Stem cell factor (SCF), the c-kit receptor ligand, plays a critical role in mast cell (MC) development and differentiation. In addition, SCF has recently been found to both modulate and induce MC activation. To investigate the effect of SCF on canine cutaneous MC function, we have characterized the ability of SCF to modulate the release by mature canine MC of preformed (histamine) and newly generated (TNF-alpha) mediators. Mature MC were isolated from skin and cultured in the absence or presence of exogenous SCF (6 ng/ml) for up to 5 days and then challenged with anti-IgE (1 microg/ml) alone for 30 min or with a combination of SCF (50 ng/ml) and anti-IgE. SCF alone failed to trigger either histamine or TNF-alpha release at any time. However, we observed that SCF used as a co-stimulus significantly potentiated histamine and TNF-alpha release in canine MC activated through Fc epsilon RI regardless of whether or not SCF was added to the medium during culturing. Thus, the mean histamine release (%) and TNF-alpha production (pg/ml) were found to be significantly higher if cells were maintained in culture in SCF-supplemented medium compared with cells cultured in the absence of exogenous SCF. We also observed that MC responsiveness to immunological stimulation increased with culture time, the percentage of histamine released being higher in cells cultured for at least 3 days when compared to freshly isolated MC. Taken together these findings suggest that canine skin MC releasability can be enhanced independently either through prolonged incubation with SCF and/or through anti-IgE and SCF co-stimulation.
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PMID:Stem cell factor enhances IgE-mediated histamine and TNF-alpha release from dispersed canine cutaneous mast cells. 1088 2

Protein-tyrosine kinases play crucial roles in mast cell activation through the high-affinity IgE receptor (FcepsilonRI). In this study, we have made the following observations on growth properties and FcepsilonRI-mediated signal transduction of primary cultured mast cells from Btk-, Lyn-, and Btk/Lyn-deficient mice. First, Lyn deficiency partially reversed the survival effect of Btk deficiency. Second, FcepsilonRI-induced degranulation and leukotriene release were almost abrogated in Btk/Lyn doubly deficient mast cells while singly deficient cells exhibited normal responses. Tyrosine phosphorylation of cellular proteins including phospholipases C-gamma1 and C-gamma2 was reduced in Btk/Lyn-deficient mast cells. Accordingly, FcepsilonRI-induced elevation of intracellular Ca2+ concentrations and activation of protein kinase Cs were blunted in the doubly deficient cells. Third, in contrast, Btk and Lyn demonstrated opposing roles in cytokine secretion and mitogen-activated protein kinase activation. Lyn-deficient cells exhibited enhanced secretion of TNF-alpha and IL-2 apparently through the prolonged activation of extracellular signal-related kinases and c-Jun N-terminal kinase. Potentially accounting for this phenomenon and robust degranulation in Lyn-deficient cells, the activities of protein kinase Calpha and protein kinase CbetaII, low at basal levels, were enhanced in these cells. Fourth, cytokine secretion was severely reduced and c-Jun N-terminal kinase activation was completely abrogated in Btk/Lyn-deficient mast cells. The data together demonstrate that Btk and Lyn are involved in mast cell signaling pathways in distinctly different ways, emphasizing that multiple signal outcomes must be evaluated to fully understand the functional interactions of individual signaling components.
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PMID:Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation. 1090 18

In the present study we show the capacity of an extract of the fern Polypodium leucotomos (PLE) to partially inhibit the production of cytokines showing a Th1 pattern (IL-2, IFN-gamma and TNF-alpha) in human PHA-stimulated peripheral blood mononuclear cells. The percentage of inhibition was 24% for IL-2, 72% for INF-gamma and 53% for TNF-alpha. With regard to Th2 cytokines, the addition of PLE resulted in a significant increase (33%) in IL-10 production. Surprisingly, the production of the inflammatory cytokine IL-6 was completely abolished (100% inhibition) by PLE at all doses tested. In a second experiment in vivo we show that, the topical application of PLE to the skin of hairless albino mice (Skh-1) significantly diminished the mast cell infiltrate as well as the number of blood vessels triggered by chronic ultraviolet B (UVB) irradiation. These data show that PLE moderately inhibits the immunological Th1 responses, thus explaining the immunosuppressive as well as the anti-inflammatory and antioxidant activities reported in other studies carried out with PLE. The clear inhibitory effect on TFN-alpha and IL-6 production strongly suggest that this may be the mechanism by which PLE: (a) inhibits angiogenesis in vivo in the mouse model described here, and (b) prevents Langerhans' cells depletion caused by solar irradiation in humans. Taken together, these data suggest that PLE works through the induction of suppressive/anti-inflammatory cytokines such as IL-10 and/or TGF-beta which in turn appear to allow the partial deactivation of macrophages or other accessory cells. These features suggest that PLE could be useful in the treatment of autoaggressive/inflammatory conditions due to an exacerbation of Th1 responses.
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PMID:An extract of the fern Polypodium leucotomos (Difur) modulates Th1/Th2 cytokines balance in vitro and appears to exhibit anti-angiogenic activities in vivo: pathogenic relationships and therapeutic implications. 1092 72

Mast cells can be found in contact with epidermis in certain circumstances; especially in chronic inflammatory skin diseases and chronic ulcers, but the significance of this association is obscure. In this study, the association of mast cells with wound healing was studied by counting mast cells in the wound edges at different stages after wounding the donor site skin for pinch-grafting. Chronic venous leg ulcers were biopsed for comparison. Tryptase- and chymase-positive mast cells were stained enzyme-histochemically for active proteinases. Both the number of tryptase-positive, i.e. total mast cells, and chymase-positive mast cells decreased during wound healing, but only the change in chymase-positive mast cells was statistically significant (P< or =0.03) the maximal decrease being 63% on day 7. No mast cells could be found in the vicinity of epithelialization margin. In venous leg ulcers, significantly more mast cells were present in the perilesional skin near the epithelium margin than in the wound bed (P=0.03), and mast cells were also seen in close contact with the basement membrane. Immunoreactivity for IL-4 and TNF-alpha in mast cells was studied to see if either of these molecules was associated with wound healing. In normally healing wounds, only a minority of mast cells were immunoreactive for these cytokines and no change in positive mast cell numbers could be seen during wound healing. In chronic wounds, IL-4 was absent in mast cells, and TNF-alpha positive mast cells were present only in perilesional skin and in small numbers. These results show that mast cells especially chymase-positive - decrease in number and can not be found in the epithelialization zone in normal wound healing, whereas tryptase-positive mast cells are associated with delayed wound healing and epithelialization in chronic wounds. Thus it seems, that mast cells attempt to control hyperproliferation of epidermis in chronic wounds.
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PMID:Alterations in mast cells showing tryptase and chymase activity in epithelializating and chronic wounds. 1094 47

In the present study, we have investigated the pro-opiomelanocortin (POMC)-derived neuropeptide alpha-MSH for its ability to modulate activation of human mast cells. The in vitro ability of purified human skin mast cells to secrete various types of mast cell mediators was monitored in response to alpha-MSH at the mRNA and at the protein level. Picomolar concentrations of alpha-MSH induced a dose-dependent release of histamine from isolated human skin mast cells and from skin punch biopsies. However, no effect of alpha-MSH was seen regarding the expression of IL-1, IL-6, IL-8, TGF-beta, and TNF-alpha. Melanocortin receptor MC-1 was identified at the transcriptional level by RT-PCR analysis but not at the protein level, whereas, in leukemic human mast cells (HMC-1), the mRNAs and the proteins for the MC-1 and MC-5 receptor were identified. These results suggest that alpha-MSH may selectively induce acute inflammatory effects via secretion of histamine.
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PMID:alpha-Melanocyte stimulating hormone acts as a selective inducer of secretory functions in human mast cells. 1107 48


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