Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allergic rhinitis is an increasing problem for which new and exciting therapies are being developed. These can be understood through an appreciation of the newer concepts of pathogenesis of allergic rhinitis. Allergen induces Th2 lymphocyte proliferation in persons with allergies with the release of their characteristic combination of cytokines including IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13. These substances promote IgE and mast cell production. Mucosal mast cells that produce IL-4, IL-5, IL-6, and tryptase proliferate in the allergic epithelium. Inflammatory mediators and cytokines upregulate endothelial cell adhesion markers, such as vascular cell adhesion molecule-1. Chemoattractants, including eotaxin, IL-5, and RANTES, lead to characteristic infiltration by eosinophils, basophils, Th2 lymphocytes, and mast cells in chronic allergic rhinitis. As our understanding of the basic pathophysiologic features of allergic rhinitis continues to increase, the development of new diagnostic and treatment strategies may allow more effective modulation of the immune system, the atopic disease process, and the associated morbidity.
 ...
PMID:Pathogenesis of allergic rhinitis. 904 69

Mast cells are a heterogeneous family of immune cells that, when activated through their high affinity IgE receptors (Fc epsilonRI), release various granule mediators (e.g., neutral proteases and serglycin proteoglycans) and proinflammatory cytokines (e.g., IL-6 and TNF-alpha). We and others have shown that the growth and differentiation of immature, nontransformed mouse bone marrow-derived mast cells (mBMMC) can be regulated in vitro by IL-3, IL-10, and c-kit ligand. We now report that glucocorticoids inhibit the c-kit ligand- and IL-3-induced proliferation of mBMMC, the Fc epsilonRI-mediated expression of TNF-alpha, and the IL-10-mediated expression of the two chymases designated mouse mast cell protease (mMCP)-1 and mMCP-2. In contrast, glucocorticoids induce mBMMC to increase their expression of serglycin proteoglycan and carboxypeptidase A. As assessed by nuclear run-on and RNA blot analyses, dexamethasone inhibited the IL-10-mediated expression of mMCP-1 and mMCP-2, primarily by inducing rapid degradation of their transcripts. The stimulative effect on serglycin proteoglycan expression and the inhibitory effect on chymase expression were dose and time dependent and glucocorticoid specific. These findings indicate that glucocorticoids exert profound and diverse effects on the growth, cytokine expression, and granule differentiation of mouse mast cells, and that at least some of this regulation occurs through a post-transcriptional mechanism.
 ...
PMID:Glucocorticoids inhibit the cytokine-induced proliferation of mast cells, the high affinity IgE receptor-mediated expression of TNF-alpha, and the IL-10-induced expression of chymases. 912 1

When stimulated through IgE-(or IgG-) immune complexes with parasite antigens, mast cells can release several cytokines, including IL-4, IL-6, IL-10, IL-12, Interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) that may influence the host response to Leishmania major in modulating lesion size and persistence during experimental infection in the mouse. Moreover, recent data demonstrated that mast cells are able to be antibody-independently activated by direct contact with bacteria, making them important elements in innate immunity. Given these data, we asked whether cell-parasite contact could directly induce mast cell mediator release and whether mast cells could be infected by L. major or L. infantum parasites. In this study, we showed that a pure homogeneous population of mouse bone marrow derived mast cells (BMMC) in contact with living L. major or L. infantum promastigotes, but not with attenuated parasites or soluble parasite antigens, released preformed mediators such as beta-hexosaminidase and the preformed pool of TNF-alpha within minutes. Furthermore, direct cell-parasite contact induced TNF-alpha synthesis by mast cells within hours. Moreover, we demonstrated by in vitro co-culture experiments that metacyclic L. major or L. infantum promastigotes are directly infective for a significant proportion of BMMC and are transformed into intracellular amastigotes. Taken together, these data suggest that mast cell can participate in the first line of defence, i.e. innate immunity, during local cutaneous infection with Leishmania parasites.
 ...
PMID:Evidence for direct interaction between mast cells and Leishmania parasites. 937 16

Recent evidence has been accumulated to suggest that allergen-reactive type 2 helper T cells (Th2) play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, i.e. the cellular triad involved in the allergic inflammation. Interleukin (IL)-4 production by a still unknown cell type (T cell subset, mast cell/basophil?) at the time of antigen presentation to the Th cell is critical for the development of Th2 cells. Other cytokines, such as IL-1 and IL-10, and hormones, such as calcitriol and progesterone, also play a favoring role. In contrast, cytokines such as interferon (IFN-alpha, IFN-gamma, IL-12 and transforming growth factor (TGF)-beta, and hormones, play a negative regulatory role on the development of Th2 cells. However, the mechanisms underlying the preferential activation by environmental allergens of Th2 cells in atopic individuals still remain obscure. Some gene products selectively expressed in Th2 cells or selectively controlling the expression of IL-4 have recently been described. Moreover, cytokines and other gene products that dampen the production of IL-4, as well as the development and/or the function of Th2 cells, have been identified. These findings allow us to suggest that the up-regulation of genes controlling IL-4 expression and/or abnormalities of regulatory mechanisms of Th2 development and/or function may be responsible for Th2 responses against common environmental allergens in atopic people. The new insights in the pathophysiology of T cell responses in atopic diseases provide exciting opportunities for the development of novel immunotherapeutic strategies. They include the induction of nonresponsiveness in allergen-specific Th2 cells by allergen peptides or redirection of allergen-specific Th2 responses by Th1-inducing cytokines, altered peptide ligands, allergens incorporated into recombinant microorganisms or bound to appropriate adjuvants, and plasmid DNA vaccination. In severe atopic patients, the possibility of nonallergen-specific immunotherapeutic regimens designed to target Th2 cells or Th2-dependent effector molecules, such as specific IL-4 transcription factors, IL-4, IL-5 and IgE, may also be suggested.
 ...
PMID:The TH1/TH2 paradigm in allergy. 953 May 57

Tissue mast cell development requires stem cell factor (SCF), whereas helminth-induced intestinal mucosal mast cell hyperplasia also requires T cell-derived factors such as IL-3. We generated progenitor mast cells (PrMC) from mouse bone marrow cells (BMC) in vitro with a triad of SCF, IL-6, and IL-10 that exhibit IL-3-mediated mitogenic and maturation responses. SCF/IL-6/IL-10 transiently elicited a cell subpopulation with the phenotype (c-kit(high)Thy-1(low)) of fetal blood promastocytes at 3 wk of culture that progressed within 1 wk to FcepsilonRI-bearing PrMC, designated PrMCTriad. PrMCTriad lacked mouse mast cell carboxypeptidase A (mMC-CPA) protein, required SCF for IL-3-driven thymidine incorporation, and responded to SCF plus IL-3 with strong mMc-CPA immunoreactivity, clarifying distinct sequential roles for SCF and IL-3 in mast cell development. PrMCTriad, arising from BMC through promastocytes, are metamastocytes that acquire microenvironmentally determined phenotypic features.
 ...
PMID:Generation of a novel stem cell factor-dependent mast cell progenitor. 982 Apr 83

The c-kit protooncogene encodes a receptor tyrosine kinase that is known to play a critical role in hemopoiesis and is essential for mast cell growth, differentiation, and cytokine production. Studies have shown that the Th2 cytokine IL-4 can down-regulate Kit expression on human and murine mast cells, but the mechanism of this down-regulation has remained unresolved. Using mouse bone marrow-derived mast cells, we demonstrate that IL-4-mediated Kit down-regulation requires STAT6 expression and phosphotidylinositide-3'-kinase activation. We also find that the Th2 cytokine IL-10 potently down-regulates Kit expression. IL-4 enhances IL-10-mediated inhibition in a manner that is STAT6 independent and phosphotidylinositide-3'-kinase dependent. Both IL-4- and IL-10-mediated Kit down-regulation were coupled with little or no change in c-kit mRNA levels, no significant change in Kit protein stability, but decreased total Kit protein expression. Inhibition of Kit expression by IL-4 and IL-10 resulted in a loss of Kit-mediated signaling, as evidenced by reduced IL-13 and TNF-alpha mRNA induction after stem cell factor stimulation. These data offer a role for STAT6 and phosphotidylinositide-3'-kinase in IL-4-mediated Kit down-regulation, coupled with the novel observation that IL-10 is a potent inhibitor of Kit expression and function. Regulating Kit expression and signaling may be essential to controlling mast cell-mediated inflammatory responses.
 ...
PMID:Inhibition of Kit expression by IL-4 and IL-10 in murine mast cells: role of STAT6 and phosphatidylinositol 3'-kinase. 1045 90

Three orf virus putative virulence proteins are described that exhibit immunomodulatory functions. The OVIFNR gene at the left terminus of the viral genome encodes an interferon resistance protein with homology to the E3L gene of vaccinia virus. OVIFNR functions by preventing a dsRNA-dependent kinase from inhibiting virus and cell protein synthesis as part of the interferon-induced anti-viral state within infected cells. The orf virus orthologue of the ovine interleukin-10 (vIL-10) gene is located at the right terminus of the viral genome. Both vIL-10 and host (ovine) IL-10 function in vitro as inhibitors of pro-inflammatory cytokine production by keratinocytes and macrophages, and both inhibit IFN-gamma production from activated peripheral blood lymphocytes. Both the orf virus vIL-10 and ovine IL-10 stimulate mast cell and thymocyte proliferation. In this respect the orf virus IL-10 differs from Epstein Barr virus IL-10 which does not exhibit cell proliferative activity. Finally, the orf virus GM-CSF inhibitory factor gene (GIF) at the right terminus of the viral genome encodes an inhibitor of GM-CSF that also binds IL-2. Together, these viral proteins are capable of inhibiting key components of the ovine anti-virus immune and inflammatory response.
 ...
PMID:Immunomodulation by virulence proteins of the parapoxvirus orf virus. 1061 96

Mast cell hyperplasia is observed in various inflammatory skin diseases. Although the pathogenesis of these conditions remains largely uninvestigated, it has been speculated that lesional mediators provide a favorable microenvironment for mast cell growth. We investigated the effect of an inflammatory cytokine, IL-1 alpha, on mast cell growth in a mast cell/fibroblast coculture system. When mouse bone marrow-derived cultured mast cells (BMMC) were cultured on a NIH/3T3 fibroblast monolayer, IL-1 alpha stimulated mast cell proliferation. However, IL-1 alpha did not stimulate 3H-thymidine incorporation in BMMC in the absence of fibroblasts. Separation of BMMC from fibroblasts by a permeable micropore membrane reduced the effect of IL-1 alpha. When BMMC were prepared from W/Wv mice, which lack a functional c-kit, or when NIH/3T3 fibroblasts were substituted with Sl/Sld-derived fibroblasts, which lack membrane-bound stem cell factor (SCF), a lower, but significant, effect of IL-1 alpha was observed. Flow cytometric analysis revealed no enhancement of SCF expression on fibroblasts following stimulation with IL-1 alpha. Neutralizing antibodies against IL-3, IL-4, IL-10, and nerve growth factor (NGF) showed no inhibition. On the other hand, indomethacin inhibited the effect of IL-1 alpha, and prostaglandin E2 induced mast cell growth in the co-cultures. These results indicate that IL-1 alpha stimulates mast cell growth by a fibroblast-dependent mechanism, in which SCF/c-kit interaction may participate in a major way. The mast cell growth activity induced by this cytokine can, at least in part, be attributed to prostaglandins. Inflammatory cytokines may thus contribute to mast cell hyperplasia in skin diseases.
 ...
PMID:Interleukin-1 alpha enhances mast cell growth by a fibroblast-dependent mechanism. 1086 12

We have previously shown that interleukin (IL-)10-induced proliferation of the murine mast cell line D36, was dependent upon the activation of PI 3-kinase and p70 S6 kinase. Conversely, we were able to show that this pathway was not involved in the signal transduction pathway mediating IL-10 inhibition of pro-inflammatory cytokine release from monocytes. We have extended these studies to investigate the induction of p75 tumour necrosis factor receptor (TNF-R) shedding, another anti-inflammatory property of IL-10. Using the inhibitors of PI 3-kinase (LY294002 and wortmannin) and an inhibitor of p70 S6 kinase activation (rapamycin), we were able to show that this anti-inflammatory effect of IL-10 was not mediated by the PI 3-kinase/p70 S6 kinase pathway, indicating that another signalling cascade(s) was involved. Further studies also investigated the role of tyrosine kinases in the response to IL-10. Two distinct tyrosine kinase inhibitors, herbimycin and genistein affected the expression of TNF-R in response to IL-10 but, surprisingly, with opposite effects. However, both compounds inhibited the activation of both PI 3-kinase and p70 S6 kinase, with a concomitant inhibition of IL-10-induced proliferation. We observed that whilst tyrosine kinase activity was involved in the regulation of TNF-R expression, IL-10-induced activation of JAK kinases was not sensitive to inhibition by the tyrosine kinase inhibitors. These data suggest that multiple unknown tyrosine kinases are mediating the IL-10-induced signal transduction pathways leading to the regulation of TNF-R expression and IL-10-induced proliferation.
 ...
PMID:Interleukin 10 modulation of tumour necrosis factor receptors requires tyrosine kinases but not the PI 3-kinase/p70 S6 kinase pathway. 1088 Feb 38

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.
 ...
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


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>