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)

There is a direct correlation between dermal mast cell prevalence in dorsal skin of different mouse strains and susceptibility to UVB-induced systemic immunosuppression; highly UV-susceptible C57BL/6 mice have a high dermal mast cell prevalence while BALB/c mice, which require considerable UV radiation for 50% immunosuppression, have a low mast cell prevalence. There is also a functional link between the prevalence of dermal mast cells and susceptibility to UVB- and cis-urocanic acid (UCA)-induced systemic immunosuppression. Mast cell-depleted mice are unresponsive to UVB or cis-UCA for systemic immunosuppression unless they are previously reconstituted at the irradiated or cis-UCA-administered site with bone marrow-derived mast cell precursors. cis-UCA does not stimulate mast cell degranulation directly. Instead, in support of studies showing that neither UVB nor cis-UCA was immunosuppressive in capsaicin-treated, neuropeptide-depleted mice, cis-UCA-stimulated neuropeptide release from sensory c-fibers which, in turn, could efficiently degranulate mast cells. Studies in mice suggested that histamine, and not tumor necrosis factor alpha (TNF-alpha), was the product from mast cells that stimulated downstream immunosuppression. Histamine receptor antagonists reduced by approximately 60% UVB and cis-UCA-induced systemic immunosuppression. Indomethacin administration to mice had a similar effect which was not cumulative with the histamine receptor antagonists. Histamine can stimulate keratinocyte prostanoid production. We propose that both histamine and prostaglandin E(2) are important in downstream immunosuppression; both are regulatory molecules supporting the development of T helper 2 cells and reduced expression of type 1 immune responses such as a contact hypersensitivity reaction.
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PMID:Mast cells, neuropeptides, histamine, and prostaglandins in UV-induced systemic immunosuppression. 1223 Nov 91

We assessed mast cell influence on eosinophils, the prominent cells in late and chronic allergic reactions, by comparing the proteomic pattern of eosinophils incubated with mast cells, tumor necrosis factor alpha (TNF-alpha) or granulocyte macrophage colony stimulating factor (GM-CSF). Eosinophils were incubated with the human mast cell line HMC-1 cellular sonicate and their survival and GM-CSF production were evaluated. For proteomic studies, eosinophils were cultured with HMC-1 sonicate, TNF-alpha or GM-CSF in the presence of [(35)S]methionine, solubilized and submitted to isolelectric focusing separation and sodium dodecyl sulfate polyacrylamide gel electrophoresis in the ISODALT system, followed by radiofluorography and computer image analysis. HMC-1-incubated eosinophils displayed increased survival partly mediated by mast cell-associated TNF-alpha, and produced GM-CSF. Metabolically labeled eosinophils incubated with either HMC-1, TNF-alpha or GM-CSF released eosinophil peroxidase. Comparison of two-dimensional gel spots from the eosinophils revealed that each of the three activating signals yielded a distinctly different proteomic pattern of labeled polypeptides. GM-CSF provided the strongest signal and the highest rate of protein synthesis (1,018 spots) followed by TNF-alpha (747 spots) and HMC-1 sonicate (611 spots). A portion of spots differed both in terms of quality and quantity. Although each stimulus induced similar functional effects, the resulting biosynthetic programs of the eosinophils greatly differed. The presented proteomic analysis is the first step in the exploration of molecular mechanisms involved in eosinophil activation.
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PMID:Proteomic analysis of human eosinophil activation mediated by mast cells, granulocyte macrophage colony stimulating factor and tumor necrosis factor alpha. 1244 59

The effects of adenosine receptor agonists on cytokine production in vivo were investigated in mouse models of endotoxemia. Selective adenosine A(3) (2-chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methyluronamide) (2-Cl-IB-MECA) and A(2A) (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride) (CGS 21860) receptor agonists were found to modulate endotoxin-induced cytokine responses in mice sensitized to D-galactosamine or primed with Corynebacterium parvum. The adenosine receptor agonists had similar effects in these models of endotoxemia, suppressing the production of tumor necrosis factor alpha (TNF-alpha) and interleukin-12 while enhancing that of interleukin-10. However, 2-Cl-IB-MECA also caused a dramatic increase in circulating histamine levels shortly after its injection into mice. The cytokine modulatory activities of 2-Cl-IB-MECA were mimicked by the mast cell depleting compound 48/80 and both drugs only produced such effects at doses that caused an elevation in circulating histamine levels. Furthermore, the capacity of 2-Cl-IB-MECA to modulate cytokine responses was greatly diminished when the drug was administered to mast cell deficient (WBB6F-W/W(V)) mice. Together, these results strongly suggest a role for histamine in cytokine modulation by 2-Cl-IB-MECA. Cimetidine, a histamine H(2) receptor antagonist, did not reverse cytokine modulation by 2-Cl-IB-MECA and pyrilamine, a histamine H(1) receptor antagonist, prevented the increase in serum histamine that was induced by 2-Cl-IB-MECA. This effect of pyrilamine and other histamine H(1) receptor antagonists confounded attempts to determine a role for the histamine H(1) receptor in cytokine modulation by 2-Cl-IB-MECA. However, under some experimental conditions, pyrilamine appeared to antagonize the modulatory effects of the adenosine A(3) receptor agonist on cytokine responses. The apparent antagonism of pyrilamine was unrelated to its suppressive effects on histamine release and appeared to reflect activity at the level of the histamine H(1) receptor.
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PMID:A role for histamine in cytokine modulation by the adenosine A(3) receptor agonist, 2-Cl-IB-MECA. 1246 Jun 44

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

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

Transmembrane metalloproteinases of the disintegrin and metalloproteinase (ADAM) family control cell signaling interactions via hydrolysis of protein extracellular domains. Prior work has shown that the receptor tyrosine kinase, c-Kit (CD117), is essential for mast cell survival and that serum levels of c-Kit increase in proliferative mast cell disorders, suggesting the existence of c-Kit shedding pathways in mast cells. In the present work, we report that tumor necrosis factor alpha-converting enzyme (TACE; ADAM-17) mediates shedding of c-Kit. Stimulation of transfected cells with phorbol 12-myristate 13-acetate (PMA) induced metalloproteinase-mediated release of c-Kit ectodomain, which increased further upon TACE overexpression. By contrast, TACE-deficient fibroblasts did not demonstrate inducible release, thus identifying TACE as the metalloproteinase primarily responsible for PMA-induced c-Kit shedding. Surface expression of c-Kit by the human mast cell-1 line decreased upon phorbol-induced shedding, which involved metalloproteinase activity susceptible to inhibition by tissue inhibitor of metalloproteinase (TIMP)-3. To further explore the role of TACE in shedding of c-Kit from mast cells, we compared the behavior of mast cells derived from murine embryonic stem cells. In these studies, PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (DeltaZn/DeltaZn), confirming the role of TACE in PMA-induced c-Kit shedding. Compared with TACE(+/+) cells, TACE(DeltaZn/DeltaZn) mast cells also demonstrated decreased constitutive shedding and increased basal surface expression of c-Kit, with diminished apoptosis in response to c-Kit ligand deprivation. These data suggest that TACE controls mast cell survival by regulating shedding and surface expression of c-Kit.
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PMID:Tumor necrosis factor-alpha-converting enzyme controls surface expression of c-Kit and survival of embryonic stem cell-derived mast cells. 1462 90

Increasing evidence has revealed that mast cell-derived tumor necrosis factor alpha (TNF-alpha) plays a critical role in a number of inflammatory responses by recruiting inflammatory leukocytes. In this paper, we investigated the regulatory role of interleukin 4 (IL-4) in TNF-alpha production in mast cells. IL-4 inhibited immunoglobulin E-induced TNF-alpha production and neutrophil recruitment in the peritoneal cavity in wild-type mice but not in signal transducers and activators of transcription 6 (Stat6)-deficient mice. IL-4 also inhibited TNF-alpha production in cultured mast cells by a Stat6-dependent mechanism. IL-4-Stat6 signaling induced TNF-alpha mRNA destabilization in an AU-rich element (ARE)-dependent manner, but did not affect TNF-alpha promoter activity. Furthermore, IL-4 induced the expression of tristetraprolin (TTP), an RNA-binding protein that promotes decay of ARE-containing mRNA, in mast cells by a Stat6-dependent mechanism, and the depletion of TTP expression by RNA interference prevented IL-4-induced down-regulation of TNF-alpha production in mast cells. These results suggest that IL-4-Stat6 signaling induces TTP expression and, thus, destabilizes TNF-alpha mRNA in an ARE-dependent manner.
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PMID:IL-4-Stat6 signaling induces tristetraprolin expression and inhibits TNF-alpha production in mast cells. 1463 48

Intercellular adhesion molecule-1 (ICAM-1) has been shown to play crucial roles in mast cell interaction with other inflammatory cells and recruitment into the inflamed tissue. In the present study, human mast cell line-1 (HMC-1) was stimulated with different cytokines including stem cell factor (SCF), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-13, IL-18, and IL-25. Cell-surface expression of ICAM-1 was assessed by flow cytometry. To elucidate the intracellular signal transduction regulating the ICAM-1 expression, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-kappaB translocation were assessed by enzyme-linked immunosorbent assay. Results showed that SCF, TNF-alpha, and IL-13 but not IL-18 and IL-25 could up-regulate the surface expression of ICAM-1 on HMC-1 cells. A synergistic effect of SCF and TNF-alpha on ICAM-1 expression was demonstrated. This synergistic effect was shown to be dose-dependently enhanced by SCF but not TNF-alpha. Results indicated that SCF activated ERK, and TNF-alpha activated the p38 MAPK and NF-kappaB pathway. Selective inhibitor of ERK, PD098059, and c-kit inhibitors, STI571 and PP1, suppressed the combined SCF and TNF-alpha-induced ICAM-1 expression. BAY117082 but not SB203580, which are the inhibitors of NF-kappaB and p38 MAPK, respectively, suppressed the TNF-alpha-induced ICAM-1 expression. Therefore, SCF and TNF-alpha acted through ERK and the NF-kappaB pathway to regulate the ICAM-1 expression and elicited the synergistic effect. In conclusion, our results provide insight for cross-talk between different signaling pathways that can help in understanding the fine control of adhesion molecule expression under the concerted effects of cytokines.
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PMID:Synergistic effect of SCF and TNF-alpha on the up-regulation of cell-surface expression of ICAM-1 on human leukemic mast cell line (HMC)-1 cells. 1580 27

Mast cells are fascinating, multifunctional, tissue-dwelling cells that have been traditionally associated with the allergic response. However, recent studies suggest these cells may be capable of regulating inflammation, host defense, and innate immunity. The purpose of this review is to present salient aspects of mast cell biology in the context of mast cell function in physiology and disease. After their development from bone marrow-derived progenitor cells that are primed with stem cell factor, mast cells continue their maturation and differentiation in peripheral tissue, developing into two well-described subsets of cells, MC(T) and MC(TC) cells. These cells can be distinguished on the basis of their tissue location, dependence on T lymphocytes, and their granule contents. Mast cells can undergo activation by antigens/allergens, superoxides, complement proteins, neuropeptides, and lipoproteins. After activation, mast cells express histamine, leukotrienes, and prostanoids, as well as proteases, and many cytokines and chemokines. These mediators may be pivotal to the genesis of an inflammatory response. By virtue of their location and mediator expression, mast cells may play an active role in many diseases, such as allergy, parasitic diseases, atherosclerosis, malignancy, asthma, pulmonary fibrosis, and arthritis. Recent data also suggest that mast cells play a vital role in host defense against pathogens by elaboration of tumor necrosis factor alpha. Mast cells also express the Toll-like receptor, which may further accentuate their role in the immune-inflammatory response. This chapter summarizes the many well-known and novel functional aspects of human mast cell biology and emphasizes their unique role in the inflammatory response.
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PMID:The human mast cell: an overview. 1611 Jan 46

The possible role of mast cell in neutrophil migration failure during sepsis was examined in a polymicrobial sepsis model in mice. Mast cells were depleted by compound 48/80 or lysed by distilled water, both preventing the neutrophil migration failure. This phenomenon was accompanied by reduction of bacteria in the peritoneal cavity and blood, serum tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and nitrate (NO3) and by an increase in mice survival rate. Neither neutrophil migration failure nor significant mortality was observed when lethal inoculum was injected into the air-pouch model, a cavity poorly populated by mast cells. Confirming that neutrophil migration failure is a phenomenon induced by systemic circulating mediators, it was observed that i.p. administration of lethal inoculum induced a neutrophil migration failure to the air pouch inoculated with non-lethal bacterial challenge. These results suggest that mast cells have a key role in the genesis of neutrophil migration failure, and, consequently, contribute to the systemic inflammatory response and mortality in severe sepsis.
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PMID:Effect of mast cells depletion on the failure of neutrophil migration during sepsis. 1626 1


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