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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)-antigen interactions is promoted by T helper cell type 2 (Th2) cytokines and leads to the sequelae of allergic disease. We now report a mechanism by which Th2 cytokines can regulate mast cell survival. Specifically, we find that interleukin (IL)-4 and IL-10 induce apoptosis in IL-3-dependent bone marrow-derived mast cells and peritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of transcription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl-x(L) and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated death. Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3-independent mastocytomas and mast cell lines were resistant to apoptosis induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine-mediated homeostasis whereby these cytokines both elicit and limit allergic responses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.
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PMID:Combined stimulation with the T helper cell type 2 cytokines interleukin (IL)-4 and IL-10 induces mouse mast cell apoptosis. 1103 99

It has been established that mast cells can alter their expression of granule chymases and tryptases in vivo. In vitro, a reversible cytokine regulation has so far only been demonstrated for chymases. We now show a reversible and cytokine-regulated expression of the tryptases MMCP-6 and MMCP-7 and of the chymases MMCP-1, MMCP-2 and MMCP-4 in the continuous murine mast cell line L138.8A. The L138.8A mast cells lacked expression of mRNA for mast cell-specific proteases when cultured in IL-3, and only 49% and 41% of the cells were c-kit+ and FcepsilonRI+, respectively, by flow cytometry. Kit-ligand/stem cell factor induced synthesis of the chymase MMCP-4 and the tryptases MMCP-6 and MMCP-7 and increased the fraction of c-kit+ and FcepsilonRI+ L138.8A cells to >70%. Kit-ligand-induced tryptase expression was suppressed in the presence of IL-3 or IL-9, and reversed after withdrawal of kit-ligand. IL-9 or IL-3/IL-10 promoted the formation of Alcian blue+ granules and increased the fraction of c-kit+ and FcepsilonRI+ L138.8A cells to >90%. IL-9 further induced the expression of the chymases MMCP-1, MMCP-2 and MMCP-4. Thus, the immature mast cell line L138.8A has the capacity to modulate both tryptase and chymase expression and represents the first model system to analyze the molecular regulation of tryptase expression in vitro.
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PMID:Reversible expression of tryptases in continuous L138.8A mast cells. 1106 78

PGE(2) is an endogenously synthesized inflammatory mediator that is over-produced in chronic inflammatory disorders such as allergic asthma. In this study, we investigated the regulatory effects of PGE(2) on mast cell degranulation and the production of cytokines relevant to allergic disease. Murine bone marrow-derived mast cells (BMMC) were treated with PGE(2) alone or in the context of IgE-mediated activation. PGE(2) treatment alone specifically enhanced IL-6 production, and neither induced nor inhibited degranulation and the release of other mast cell cytokines, including IL-4, IL-10, IFN-gamma, and GM-CSF. IgE/Ag-mediated activation of BMMC induced the secretion of IL-4, IL-6, and GM-CSF, and concurrent PGE(2) stimulation synergistically increased mast cell degranulation and IL-6 and GM-CSF, but not IL-4, production. A similar potentiation of degranulation and IL-6 production by PGE(2), in the context of IgE-directed activation, was observed in the well-established IL-3-dependent murine mast cell line, MC/9. RT-PCR analysis of unstimulated MC/9 cells revealed the expression of EP(1), EP(3), and EP(4) PGE receptor subtypes, including a novel splice variant of the EP(1) receptor. Pharmacological studies using PGE receptor subtype-selective analogs showed that the potentiation of IgE/Ag-induced degranulation and IL-6 production by PGE(2) is mediated through EP(1) and/or EP(3) receptors. Our results suggest that PGE(2) may profoundly alter the nature of the mast cell degranulation and cytokine responses at sites of allergic inflammation through an EP(1)/EP(3)-dependent mechanism.
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PMID:Prostaglandin E2 selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through an EP1/EP3-dependent mechanism. 1108 97

Homeostatic mechanisms regulating mast cell numbers and function in peripheral tissues have largely focused on cytokines, such as stem cell factor, interleukin (IL)-3, IL-4, and IL-10, which regulate mast cell maintenance and proliferation. Despite these advances, little attention has been paid to the mechanisms that mediate mature mast cell turnover, and control of mast cell hyperplasia generated during Th2-mediated responses. These are important issues, as mast cells are now known to be multi-functional effector cells, that have the capacity to mediate both innate and Th2-induced immune responses. Numerous secretagogues may elicit mast cells to release a large number of important mediators that can cause chronic inflammation. Therefore, how mast cell homeostasis is regulated may have significant effects on normal physiology, and contribute to the genesis of inflammatory disease. Our laboratory has characterized an in vitro model of mast cell homeostasis, by which long-term exposure of murine bone-marrow-derived mast cells to the Th2-derived cytokines IL-3, IL-4, and IL-10, will induce downregulation of critical mast cell effector proteins such as Kit and Fcepsilon-RI, followed by mast cell apoptosis. These data offer a novel role for Th2 cytokines, acting to both initiate and resolve mast cell activation and proliferation. Loss of these signals may contribute to a multitude of diseases, such as mastocytosis and allergy
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PMID:The role of Th2 cytokines in mast cell homeostasis. 1129 31

The deleterious effects of ultraviolet B radiation (UVR) on cutaneous immunity are mediated in part by cytokines released from cutaneous cells following radiation exposure. On the one hand, TNF-alpha has been advocated as the primary mediator of failed contact hypersensitivity induction, and, on the other hand, IL-10 has been held responsible for tolerance. While keratinocytes exposed to UVR have been found to produce both TNF-alpha and IL-10, there is reason to question whether these major cellular constituents of the epidermis are the relevant source of immunomodulatory cytokines after UVR. Dermal mast cells also produce TNF-alpha and IL-10, and we have recently reported that mast cell-derived TNF-alpha is required for UVR-induced impairment of CH induction. In this study, we have examined whether mast cells are also a relevant source of IL-10 in UVR-dependent tolerance. We found that (a) UVR fails to induce tolerance in mast cell-deficient mice, and (b) that tolerance occurs if mast cells are triggered to degranulate after ligation of the IgE receptor. Both types of tolerance were neutralized with anti-IL-10 antibodies, are hapten specific, and are associated with regulatory lymphoid cells. We conclude that mast cells are required in UVR-induced tolerance and may be one of the major sources of IL-10 that mediates the tolerance induced by acute, low-dose UVR.
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PMID:Hapten-specific tolerance induced by acute, low-dose ultraviolet B radiation of skin requires mast cell degranulation. 1138 18

In several allergic, autoimmune, and infectious diseases, fibrosis is a major cause of morbidity and mortality. Here, using a model of infection-induced liver fibrosis, we show that interleukin (IL)-13 is required at all stages of Schistosomiasis mansoni infection to induce fibrosis. IL-4 production was preserved in IL-13-deficient mice, yet failed to significantly contribute to the fibrotic response in either acute or chronic infection. Significant fibrosis develops in all infected mice, although the magnitude of the response varies widely in inbred mice. C3H/HeN, BALB/c, and C57BL/6 mice develop high, intermediate, and low levels of fibrosis, respectively. Despite these differences, IL-13 antagonism resulted in a marked amelioration of fibrosis in all strains. The fibrotic mechanism in the high- and low-responder strains was unrelated to their tissue eosinophil or mast cell responses, but did correlate with their patterns of IL-13, IL-10, and interferon gamma (IFN-gamma) mRNA expression. Indeed, severe fibrosis correlated with a high IL-13 and low IFN-gamma/IL-10 mRNA response. Because fibrotic diseases are typically progressive disorders, an important issue was to determine whether IL-13 inactivation might be used to treat an established and ongoing fibrotic disease. Here, IL-13 antagonism was highly efficacious, even after fibrosis and the Th2 cytokine response were firmly established. These studies demonstrate the central role played by IL-13 in fibrogenesis and suggest that therapeutic approaches aimed at disrupting the IL-13 pathway will be highly effective at preventing fibrotic disease caused by chronic Th2-mediated inflammatory reactions.
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PMID:Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. 1148 12

In this work we analyzed by RT-PCR, the mRNA changes for IL-4, IL-10, TNF and IFN (induced by TSL-1 antigens in a rat mast cell line (HRMC) with mucosal characteristics. The data obtained showed an increase of 65 and 52% in mRNA expression for IL-4 and TNF respectively and a decrease of 59 and 55% in mRNAs for IFN gamma and IL-10. Our results suggest that TSL-1 antigens induce the release from MC of regulatory molecules, such as IL-4 by an IgE independent mechanism. Our data also provides important information related to the ability of MC to participate not only in the effector phase against the infectious agents, but also in the orchestration of the immune response by the host against parasites.
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PMID:Interleukin mRNA changes in mast cells stimulated by TSL-1 antigens. 1148 31

Mast cells are critical components of innate and adaptive immunity that differentiate in tissues in situ from circulating committed progenitor cells. We now demonstrate that human cord blood-derived mast cell progenitors are susceptible to infection with macrophagetropic (M-tropic) and dualtropic human immunodeficiency virus type 1 (HIV-1) isolates but not with T-cell-tropic (T-tropic) strains. Mast cell progenitors (c-kit(+) CD13(+) cells with chloroacetate esterase activity) were purified from 4-week-old cultures of cord blood mononuclear cells maintained in stem cell factor, interleukin-6 (IL-6), and IL-10 using a CD14 depletion column. These progenitors expressed CCR3, CCR5, and CXCR4, as well as low levels of CD4. When infected in vitro with viruses pseudotyped with different HIV and simian immunodeficiency virus envelope glycoproteins, only M-tropic and dualtropic, but not T-tropic, viruses were able to enter mast cell progenitors. Both the CCR5-specific monoclonal antibody 2D7 and TAK-779, a nonpeptide inhibitor of CCR5-mediated viral entry, blocked HIV-1 strain ADA infection by >80%. Cultures infected with replication-competent virus produced progressively increasing amounts of virus for 21 days as indicated by p24 antigen detection. Mast cell progenitors that were exposed to an M-tropic, green fluorescent protein-expressing HIV-1 strain exhibited fluorescence indicative of viral entry and replication on a single-cell level and retained virus production during differentiation. The trafficking of mast cell progenitors to multiple tissues, combined with the long life span of mature mast cells, suggests that they could provide a widespread and persistent HIV reservoir in AIDS.
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PMID:Human Mast cell progenitors can be infected by macrophagetropic human immunodeficiency virus type 1 and retain virus with maturation in vitro. 1160 22

A case of ovarian fibrosarcoma producing multiple cytokines is presented. The tumor occurred in the left ovary of a Japanese woman with epigastralgia, remittent fever, leukocytosis and slight thrombocytosis with moderate increase of mast cells in bone marrow, but lack of hormonal abnormality. The resected tumor of the ovary was well encapsulated and it was composed of spindle-shaped tumor cells and scattered tubules with marked mast cell infiltration. The tumor recurred in the pelvic cavity 14 months later, accompanied by similar signs and symptoms as occurred with the primary tumor. Serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were elevated. The recurrent tumor showed similar histological findings to those of the primary tumor, except for lack of tubules. Tumor cells revealed a focally positive immunoreaction for vimentin, IL-6 and TNF-alpha and alpha-inhibin. Reverse transcription-polymerase chain reaction using total RNA obtained from the recurrent tumor demonstrated mRNA expression of IL-6, IL-10, TNF-alpha and stem cell factor. This is a rare case of ovarian fibrosarcoma producing multiple cytokines, resulting in atypical clinical findings.
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PMID:Ovarian fibrosarcoma producing multiple cytokines. 1169 80

In this study, we characterized the differential receptor-binding specificity, affinity, and Janus kinase-STAT activation of cellular IL-10 (cIL-10) compared with viral IL-10 (vIL-10). Only cells expressing IL-10R1 bind human IL-10 or vIL-10. IL-10R2 does not bind to cIL-10 or vIL-10 alone and its presence does not enhance the receptor-binding affinity of cIL-10 or vIL-10, but it is essential for both cIL-10- and vIL-10-mediated signal transduction and immune regulation. Responses initiated by cIL-10 and vIL-10 were compared in B cell and mast cell lines, and demonstrated that the inability of vIL-10 to stimulate immune responses, as compared with human IL-10, is due to failure to initiate signaling. Absent signal transduction is due to low level expression of cell surface IL-10R1, since overexpressing IL-10R1 allows vIL-10 to initiate cIL-10-like signals and subsequent biological responses. These results are similar in primary cells, since splenocytes respond to both cIL-10 and vIL-10, while thymocytes respond only to cIL-10 and have very low mouse IL-10R1 but not mouse IL-10R2 expression. These data demonstrate that IL-10R1 expression plays a critical role in determining whether cells respond to IL-10. Modulation of cell surface IL-10R1 density might be an important mechanism for determining whether IL-10 leads to immunostimulation or immunosuppression in vivo.
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PMID:Differential IL-10R1 expression plays a critical role in IL-10-mediated immune regulation. 1173 6


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