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 can induce mast cell proliferation and melanocyte activation. Vasoactive intestinal peptide has been suggested to play a part in inflammatory dermatoses, such as atopic dermatitis. The aim of this study was to investigate the possible role of stem cell factor in atopic dermatitis by analyzing epidermal stem cell factor production induced by vasoactive intestinal peptide and cytokines. Full-length type stem cell factor transcript was detected in normal human epidermal keratinocytes, and a human epidermal keratinocyte cell line DJM-1, as well as normal human dermal fibroblasts, using reverse transcription-polymerase chain reaction. Spliced-type stem cell factor transcript was detected in both DJM-1 cells and normal human epidermal keratinocytes. Western blot analysis with stem cell factor antibody revealed a protein of the known molecular size of membrane-bound stem cell factor in the lysates of all three cell types. Stem cell factor immunoreactivity was found in the cytoplasm and the membrane of both DJM-1 cells and normal human epidermal keratinocytes using confocal laser scanning microscope. We examined the effects of vasoactive intestinal peptide and cytokines on stem cell factor production of DJM-1 cells using enzyme-linked immunosorbent assays. Stem cell factor contents significantly increased in culture supernatants of DJM-1 cells treated with 1000 nm vasoactive intestinal peptide and/or cytokines, including interleukins 4 and 13, tumor necrosis factor-alpha, and interferon-gamma. Overall, these results suggest that several inflammatory cytokines (T helper 1 and 2) and vasoactive intestinal peptide from mast cells and nerve endings are capable of inducing stem cell factor production from epidermal keratinocytes in atopic dermatitis.
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PMID:Vasoactive intestinal peptide and cytokines enhance stem cell factor production from epidermal keratinocytes DJM-1. 1244 10

The haemopoietic-restricted Src homology 2-containing inositol 5'-phosphatase (SHIP) acts as a negative regulator of myeloid cell proliferation, survival and end-cell activation. It does so, at least in part, by hydrolysing the phosphoinositide 3-kinase (PI3K)-generated second messenger, PtdIns(3,4,5) P (3) (PI-3,4,5-P(3)) to PtdIns(3,4) P (2). As a result, the myeloid progenitors in SHIP-knockout mice display enhanced survival and proliferation and the mice have increased numbers of neutrophils and monocytes/macrophages. Interestingly, although SHIP is not required for mast cell or macrophage development, it restrains their differentiation since progenitors from SHIP(-/-) mice differentiate into mature mast cells and macrophages significantly faster than their wild-type counterparts. This could suggest that elevated PI-3,4,5-P(3) levels accelerate myeloid differentiation. In bone-marrow-derived mast cells, SHIP prevents degranulation by IgE alone, restrains IgE-antigen-induced degranulation and limits the production of inflammatory cytokines. On the other hand, in peritoneal macrophages, SHIP is a positive regulator of NO production, since SHIP(-/-) peritoneal macrophages produce 5-10-fold less NO than their wild-type counterparts, even though they show greater lipopolysaccharide/interferon-gamma-induced nuclear factor kappa B activation and more rapid inducible NO synthase (iNOS) generation. This is a result of 10-fold higher levels of arginase I in the SHIP(-/-) macrophages, which redirects the iNOS substrate, L-arginine, from NO to ornithine production. This suggests that the chronically elevated PI-3,4,5-P(3) levels in SHIP(-/-) mice may convert M1 (killing) macrophages, which produce NO to kill micro-organisms and tumour cells, into M2 (healing) macrophages, which produce ornithine to promote host cell growth and fibrosis.
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PMID:Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages. 1254 3

Despite its lack of specificity, the inhibitor SB 203580 has been widely used to implicate p38 mitogen-activated protein kinase (MAPK) in the synthesis of many cytokines. Here we show unequivocally that the production of interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor alpha (TNFalpha) requires p38 MAPK activity by demonstrating that the inhibitory effects of SB 203580 were reversed by expression of an SB 203580-resistant form of p38alpha (SBR-p38alpha) that fails to bind to SB 203580. This strategy established the requirement for p38 activity for the lipopolysaccharide-stimulated production of IL-10, IL-1beta, and IL-6 by the monocytic cell WEHI 274 and the production of IL-6 and TNFalpha stimulated by ligation of the Fc-gamma receptor of the mast cell MC/9. Expression of SBR-p38alpha in primary macrophages abrogated the ability of SB 203580 to inhibit the lipopolysaccharide-stimulated production of TNFalpha but not of IL-10. Expression of SBR-p38alpha in primary T lymphocytes abrogated the ability of SB 203580 to inhibit the production of interferon-gamma induced by co-ligation of CD3 and CD28 but not the production of interferon-gamma or IL-10 induced by IL-12. These results suggest that the levels of p38 MAPK activity required for maximal cytokine production vary with different cytokines and stimuli.
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PMID:Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. 1263 77

A hapten-specific lymphocyte proliferation assay, which measures the in vitro stimulation of DNA synthesis (as assessed by [3H]thymidine incorporation), was used to determine systemic immunization induced by an epicutaneously applied hapten in addition to the more commonly used method which measures ear (or footpad) swelling. 2,4-Dinitrofluorobenzene (DNFB) was painted on the shaved backs of C57BL/6 mice for two consecutive days after ultraviolet B (UVB) irradiation (at 1000 J/m2), and DNFB-sensitized lymph node cells (LNC) were obtained from the regional lymph nodes 4 days later. Although the ear swelling response (ESR) was suppressed by UVB radiation, as previously reported, analysis of LNC culture supernatants showed that the production of interferon-gamma, a Tc1-type cytokine, was not inhibited by the UVB irradiation. In addition, contact dermatitis was induced (at levels similar to those of non-irradiated mice) by painting DNFB on the abdomen as a secondary response. We then examined the effect of UVB exposure alone on the ESR by injecting a mast cell degranulator, compound 48/80, 7 days after irradiation. Both the ESR and the percentage of degranulated mast cells were significantly reduced in UVB-irradiated mice. These results demonstrate that UVB irradiation does not affect the sensitizing phase of contact hypersensitivity, but modulates the elicitation phase and reduces the ESR primarily by suppressing the degranulation of mast cells. Therefore, suppression of the ESR alone cannot always be considered as hapten-specific immunotolerance.
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PMID:Divergence of contact hypersensitivity in vivo compared with hapten-specific lymphocyte proliferation and interferon-gamma production in vitro following ultraviolet B irradiation: the possibility that UVB does not affect the sensitizing phase of contact hypersensitivity. 1266 20

Integrins are expressed on mast cells and constitute an essential prerequisite for the accumulation of the cells at sites of inflammation. In order to clarify a potential contribution of inflammatory cytokines to this process, we have studied the modulation of integrin expression and adhesion of immature human mast cells (HMC-1) to extracellular matrix proteins by interleukin-6, tumor necrosis factor alpha, interferon-alpha and interferon-gamma. Corticosteroids were used for comparison. On fluorescence-activated cell sorter analysis, preincubation of cells for 48 h with different concentrations of interleukin-6 induced a significant, up to 40%, increase of alpha v alpha 5, CD49b (alpha 2), CD49e (alpha 5), CD49f (alpha 6), and CD51 (alpha v). In contrast, different concentrations of tumor necrosis factor alpha, interferon-alpha, interferon-gamma, and dexamethasone (10-8-10-10 M) inhibited expression of adhesion receptors by up to 60%, reaching significance for some but not all integrins. On semiquantitative polymerase chain reaction analysis, interleukin-6, the other cytokines, and corticosteroids significantly modulated expression of alpha1, alpha v and alpha 5 integrin chains at mRNA level. Functional significance of these findings was proven in adhesion assays using fibronectin, laminin, and vitronectin, with interleukin-6 causing significant enhancement of adhesion in all cases, tumor necrosis factor alpha and dexamethasone inducing significant reduction of adhesion to fibronectin and laminin, and interferon-gamma significantly inhibiting adhesion to fibronectin only. Specificity of interleukin-6-induced changes was demonstrated using antibodies against alpha1 and alpha 5 integrins in unstimulated and interleukin-6-prestimulated cells. These data show that interleukin-6 stimulates mast cell adhesion to extracellular matrix and thus allows for the accumulation of the cells at tissue sites by enhancing integrin expression, whereas tumor necrosis factor alpha, interferon-alpha, interferon-gamma, and dexamethasone downmodulate this process.
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PMID:Interleukin-6 enhances whereas tumor necrosis factor alpha and interferons inhibit integrin expression and adhesion of human mast cells to extracellular matrix proteins. 1271 84

Interleukin 18 induces both T helper 1 and T helper 2 cytokines, proinflammatory cytokines, chemokines, and IgE and IgG1 production. A role of interleukin 18 in inflammatory cutaneous reactions is still unclear, however. Here we generated keratin 5/interleukin 18 transgenic mice overexpressing mature murine interleukin 18 in the skin using a human keratin 5 promoter. In the contact hypersensitivity model, trinitrochlorobenzene elicited a stronger ear swelling in keratin 5/interleukin 18 transgenic mice compared with control littermate wild-type or immunoglobulin/interleukin 18 transgenic mice in which mature interleukin 18 was expressed by B and T cells under the control of the immunoglobulin promoter. Application of an irritant, croton oil, induced stronger and more sustained ear swelling in keratin 5/interleukin 18 transgenic mice than in immunoglobulin/interleukin 18 transgenic or wild-type mice. Repetitive topical application (weekly for six consecutive weeks) of trinitrochlorobenzene to their ears also elicited a stronger cutaneous inflammation in keratin 5/interleukin 18 transgenic mice than seen in immunoglobulin/interleukin 18 transgenic or wild-type mice. After these six trinitrochlorobenzene applications, the expression of interferon-gamma, interleukin-4, and CCL20 mRNA in the ear tissue was increased and dermal changes, such as acanthosis and eosinophilic, neutrophilic, and mast cell infiltration, were greater in keratin 5/interleukin 18 transgenic mice than in wild-type mice. Furthermore, the repetitive application elicited a significant increase in serum IgE levels and the number of B cells in the draining lymph node in keratin 5/interleukin 18 transgenic mice. These results suggest that overexpression of interleukin 18 in the skin aggravates allergic and nonallergic cutaneous inflammation, which is accompanied by high expression of T helper 1 and T helper 2 cytokines and chemokines in the skin.
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PMID:Exacerbated and prolonged allergic and non-allergic inflammatory cutaneous reaction in mice with targeted interleukin-18 expression in the skin. 1292 8

The exact pathogenesis of hypertrophic scar and keloid formation is still unknown and a good therapy to prevent or treat these scars is lacking. Because immunological processes seem to be important in excessive scar formation, immunological cells and parameters were studied in a standardized breast reduction wound-healing model in the present study. Standardized scar samples were taken from infra-mammary breast reduction scars, 3 and 12 months following surgery. The samples were investigated for their number of mast cells, Langerhans cells, T-lymphocytes, and macrophages, and the presence of interleukin-4 (IL-4) and counter-regulating interferon-gamma (gamma-IFN), in relation to the scar's clinical appearance--normal or hypertrophic. In this study, hypertrophic scar formation was significantly associated with an increased number of epidermal Langerhans cells (p=0.0001) and significantly (p<0.05) increased expression of epidermal IL-4. No relationship was found between mast cell, T-lymphocyte and macrophage numbers or gamma-IFN staining and the formation of normal or hypertrophic scars. These results, combined with previous observation of abnormal keratinocyte behaviour in this context, indicate that the epidermal immune barrier plays an important role in the development of hypertrophic scars.
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PMID:Hypertrophic scar formation is associated with an increased number of epidermal Langerhans cells. 1469 29

Mast cell activation and subsequent release of proinflammatory mediators are primarily a consequence of aggregation of the high affinity receptors for IgE (FcepsilonRI) on the mast cell surface following antigen-dependent ligation of FcepsilonRI-bound IgE. However, data obtained from rodent and human mast cells have revealed that IgG receptors (FcgammaR) can both promote and inhibit mast cell activation. These responses appear to be species and/or mast cell phenotype dependent. In CD34+-derived human mast cells exposed to interferon-gamma, FcgammaRI is upregulated, FcgammaRII is expressed but not upregulated, and FcgammaRIII is not expressed. In contrast, in mouse mast cells, FcgammaRII and FcgammaRIII receptors are expressed, whereas FcgammaRI is not. Aggregation of FcgammaRI on human mast cells promotes mediator release in a manner generally similar to that observed following FcepsilonRI aggregation. Aggregation of FcgammaRIIb in mouse mast cells fails to influence cellular processes; however, when coligated with FcepsilonRI, signaling events thus activated downregulate antigen-dependent mediator release. These divergent responses are a consequence of different motifs contained within the cytosolic tails of the signaling subunits of these receptors and the specific signaling molecules recruited by these receptors following ligation. The studies described imply that data obtained in rodent models regarding the influence of FcgammaRs on mast cells may not be directly translatable to the human. The exploitation of FcgammaRs for a potential therapy for the treatment of allergic disorders is discussed in this context.
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PMID:Fcgamma receptors on mast cells: activatory and inhibitory regulation of mediator release. 1501 13

In immunity, reactive oxygen species (ROS) and nitric oxide (NO) are important antimicrobial agents and regulators of cell signaling and activation pathways. However, the cellular sources of ROS and NO are much debated. Particularly, there is contention over whether mast cells, key secretory cells in allergy and immunity, can generate these chemical species, and if so, whether they are of functional significance. We therefore examined directly by flow cytometry the capacity of mast cells to generate intracellular ROS and NO using the respective cell-permeable fluorescent probes dichlorodihydrofluorescein and diaminofluorescein and evaluated the effects of inhibitors of ROS and NO synthesis on cell degranulation. For each of three mast cell types (rat peritoneal mast cells, mouse bone marrow-derived mast cells, and human blood-derived mast cells), degranulation stimulated by IgE/antigen was accompanied by production of intracellular ROS but not NO. Inhibition of ROS production led to reduced degranulation, indicating a facilitatory role for ROS, whereas NO synthase inhibitors were without effect. Likewise, bacterial lipopolysaccharide and interferon-gamma over a wide range of conditions failed to generate intracellular NO in mast cells, whereas these agents readily induced intracellular NO in macrophages. NO synthase protein, as assessed by Western blotting, was readily induced in macrophages but not mast cells. We conclude that rodent and human mast cells generate intracellular ROS but not NO and that intracellular ROS but not intracellular NO are functionally linked to mast cell degranulation.
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PMID:Rodent and human mast cells produce functionally significant intracellular reactive oxygen species but not nitric oxide. 1536 24

T-helper 1 (TH1) (interferon-gamma [IFN-gamma]) and TH2 (interleukin-4 [IL-4] and IL-5) cytokines have been variably reported to alter human mast cell numbers in complex culture systems. The effects of these cytokines on the kinetics of cell division and cell death are unknown, and their effect on mast cell behavior is relevant to anticipate the consequences of in vivo strategies that alter cytokine levels. To determine the effect of these cytokines on stem cell factor (SCF)-dependent human mast cell production, we used high-resolution tracking of cell division and correlated the results with cell apoptosis, expression of Kit, and mast cell degranulation. When IFN-gamma, IL-5, or IL-4 was administered over 8 weeks, we found each cytokine decreased the mast number through a different mechanism. IFN-gamma inhibited early progenitor cell division, IL-4 down-regulated early Kit expression, and IL-5 blocked later cell division. Further, IL-4 and IFN-gamma had the greatest suppressive effect on degranulation and FcepsilonRI expression. When these cytokines were administered to mature mast cells, IFN-gamma and IL-5 had no effect on degranulation and cell division, but IL-4 induced division and potentiated FcepsilonRI-mediated degranulation. Thus, exposure of human mast cells to IL-4, IL-5, and IFN-gamma during growth and differentiation generally down-regulated mast cell number and function, whereas IL-4 increased mature mast cell division and degranulation.
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PMID:High-resolution tracking of cell division demonstrates differential effects of TH1 and TH2 cytokines on SCF-dependent human mast cell production in vitro: correlation with apoptosis and Kit expression. 1536 34


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