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)

Microphthalmic (mi/mi) mice are unpigmented, osteopetrotic, mast cell deficient, and exhibit diminished gastric acid secretion and natural killer cell activity. In order to assess the effect of this mutation on macrophage function, we studied superoxide (O2-) and nitric oxide (NO) production, superoxide dismutase (SOD) activity, phagocytic capacity, and tumor cell killing by peritoneal macrophages from mi/mi mice and normal (+/+) litter mates. Macrophages from mi/mi mice, upon activation with phorbol myristate acetate (PMA), generated significantly higher amounts of O2- than did macrophages from their +/+ litter mates. The phagocyte respiratory burst as assessed by nitroblue tetrazolium (NBT) reduction assay also displayed a 2-fold enhancement in mi/mi macrophages. The assay of SOD activity revealed significantly lower levels in mi/mi macrophages than in the wild type. Furthermore, in comparison with controls, macrophages from mi/mi mice demonstrated significantly higher levels of NO production and increased capacity to lyse tumor cells upon activation with lipopolysaccharide (LPS) or gamma-interferon (IFN-gamma). The mi mutation, therefore, is associated with reduced macrophage SOD activity, increased O2- and NO production, and enhanced capacity for tumor cell killing. The molecular mechanisms for these changes have not been identified.
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PMID:Macrophage function in mice with a mutation at the microphthalmia (mi) locus. 920 63

IFN-gamma regulates various aspects of rodent peritoneal mast cell function, including mediator release, cell growth, TNF-alpha-mediated cytotoxicity, and MHC class II expression. We investigated whether the suppressive action of IFN-gamma on IgE/Ag-mediated degranulation of mast cells is mediated via synthesis of nitric oxide. Incubation of mouse peritoneal cells with L-NMMA, an inhibitor of nitric oxide synthase, or in medium lacking the nitric oxide precursor L-arginine reversed the inhibitory effect of IFN-gamma on Ag-induced serotonin release. Furthermore, the nitric oxide donors sodium nitroprusside and S-nitrosoglutathione inhibited degranulation, and this effect was direct, since it was seen equally on purified and unfractionated mast cells and occurred independently of IFN-gammaR expression. Additional experiments revealed that accessory cells in peritoneal cell populations were the principal target for the action of IFN-gamma and the main source of nitric oxide; the cytokine was more potent on unfractionated compared with purified mast cells, and IFN-gamma induced detectable nitrite production in mixed peritoneal cells, but not in purified mast cells. These studies show that IFN-gamma induces nitric oxide production in peritoneal cell populations, and that synthesized nitric oxide directly inhibits the IgE-mediated secretory function of mast cells. The activation of nitric oxide-producing cells in the tissue microenvironment may be important in the control of mast cell-dependent allergic reactions.
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PMID:Nitric oxide inhibits IgE-mediated degranulation of mast cells and is the principal intermediate in IFN-gamma-induced suppression of exocytosis. 923 42

Mucosal administration of soluble protein Ags results in profound immunologic nonresponsiveness, characterized by reduced production of Th1 and Th2 cytokines and concomitant suppressed Ig production. It has been suggested that Th2 cells are required for the induction and maintenance of this tolerogenic state. In this study, we show that oral tolerance induction abrogates subsequent Th2-driven Ag-specific IgE and IgG1 responses, while intranasal tolerance induction only blocks the production of IgE, but not IgG1. Consistent with suppressed IgE serum levels, elevated IFN-gamma production was observed in the spleens of tolerized mice. Moreover, both oral and intranasal tolerance induction were found to inhibit intestinal mast cell responses upon subsequent priming and intragastric provocation. Transfer of total splenocytes or purified CD4+, but not CD8+, T cells from intranasally tolerized mice clearly suppressed ongoing Ag-specific IgE, but not IgG1, responses in primed recipients. In addition, coadministration of IFN-gamma-neutralizing Abs completely blocked the transfer of suppression to primed recipients. These results show that Th2 cells can be subjected to tolerance induction, by inducing cross-regulatory, IFN-gamma-producing CD4+ T cells. Moreover, our results point out differences in the regulation of T cell-dependent Ag-specific IgE and IgG1 responses.
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PMID:Regulation of antigen-specific IgE, IgG1, and mast cell responses to ingested allergen by mucosal tolerance induction. 930 Jul 26

Ag-specific IgE Abs not only mediate immediate hypersensitivity through mast cell activation, but also enhance in vitro Ag presentation and in vivo specific Ab responses in mice. To delineate the role of IgE Ab in the modulation of Ag-specific responses, spleen cells from OVA-sensitized BALB/C mice were cultured together with OVA-specific IgE (or IgG isotypes). OVA-dependent proliferative responses and anti-OVA IgE production were enhanced in the presence of anti-OVA IgE. A significant decrease in IFN-gamma secretion in OVA-stimulated cultures was observed in the presence of anti-OVA IgE, but no changes in IL-4 production were detected. Anti-OVA IgG isotypes or anti-TNP IgE showed no significant effect on any of these Ag-dependent responses. Addition of anti-CD23 Ab abolished these effects of anti-OVA IgE. Further, OVA-sensitized spleen cells from CD23-deficient mice responded to in vitro stimulation with OVA, but demonstrated no modulation by anti-OVA IgE. These results demonstrate that Ag-specific IgE not only augments Ag presentation and T cell proliferation, but also alters the pattern of cytokine production and increases specific IgE synthesis. These modulatory effects of Ag-specific IgE appear to be mediated by binding to Fc epsilon RII/CD23.
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PMID:Modulation of antigen-induced B and T cell responses by antigen-specific IgE antibodies. 937 95

Interleukin 10 (IL-10) is a recently described natural endogenous immunosuppressive cytokine that has been identified in human, murine, and other organisms. Human IL-10 (hIL-10) has high homology with murine IL-10 (mIL-10) as well as with an Epstein-Barr virus genome product BCRFI. This viral IL-10 (vIL-10) shares a number of activities with hIL-10. IL-10 significantly affects chemokine biology, because human IL-10 inhibits chemokine production and is a specific chemotactic factor for CD8+ T cells. It suppresses the ability of CD4+ T cells, but not CD8+ T cells, to migrate in response to IL-8. A nonapeptide (IT9302) with complete homology to a sequence of hIL-10 located in the C-terminal portion (residues 152-160) of the cytokine was found to possess activities that mimic some of those of hIL-10. These are: (i) inhibition of IL-1beta-induced IL-8 production by peripheral blood mononuclear cell, (ii) inhibition of spontaneous IL-8 production by cultured human monocytes, (iii) induction of IL-1 receptor antagonistic protein production by human monocytes, (iv) induction of chemotactic migration of CD8+ human T lymphocytes in vitro, (v) desensitization of human CD8+ T cells resulting in an unresponsiveness toward rhIL-10-induced chemotaxis, (vi) suppression of the chemotactic response of CD4+ T human lymphocytes toward IL-8, (vii) induction of IL-4 production by cultured normal human CD4+ T cells, (viii) down-regulation of tumor necrosis factor-alpha production by CD8+ T cells, and (ix) inhibition of class II major histocompatibility complex antigen expression on IFN-gamma-stimulated human monocytes. Another nonapeptide (IT9403) close to the NH2-terminal part of hIL-10 did not reveal cytokine synthesis inhibitory properties, but proved to be a regulator of mast cell proliferation. In conclusion, we have identified two functional domains of IL-10 exerting different IL-10 like activities, an observation that suggests that relatively small segments of these signal proteins are responsible for particular biological functions.
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PMID:Identification of functional domains on human interleukin 10. 940 62

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.
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PMID:The TH1/TH2 paradigm in allergy. 953 May 57

We have previously shown that mouse bone marrow-derived mast cells (BMMC) can process and present immunogenic peptides to CD4 T cells. Here, we report on a T cell-dependent MHC class II-mediated mast cell activation resulting in IL-4 transcription and protein release. Presentation of optimal doses of ovalbumin peptide 323-339 resulted in IL-2 production by a specific T cell hybridoma and increase in IL-4 mRNA transcription in mast cells. IL-4 mRNA transcription increased by 200-fold in mast cells treated in IL-3/IL-4/granulocyte-macrophage colony-stimulating factor (high presenters) whereas only a tenfold increase or no increase were obtained with IL-3/IL-4/IFN-gamma- or IL-3-treated mast cells (low presenters), respectively. Induction of IL-4 mRNA transcription in purified mast cells by direct ligation of MHC class II molecules, using anti-I-A and anti-I-E-coated beads, indicates that MHC class II molecules are critical in this signaling pathway. However, when compared to T cells, anti-MHC class II-coated beads were less efficient, indicating a potential role of accessory molecules in this mast cell activation process. IgE-independent IL-4 production by mast cells as a result of cognate interaction with CD4 T cells could be critical for the development of type 2 responses. This novel mechanism may contribute to the induction and/or amplification of specific IgE-mediated allergic responses.
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PMID:IL-4 mRNA transcription is induced in mouse bone marrow-derived mast cells through an MHC class II-dependent signaling pathway. 954 79

Specific allergen injection immunotherapy is highly effective in selected patients with IgE-mediated disease, including respiratory allergy and venom anaphylaxis. Research in this area provides insight into the immunologic basis of allergic disease and may assist in the development of more highly targeted treatment. Immunotherapy reduces immediate allergen-induced symptoms and concentrations of inflammatory mediators, including histamine and prostaglandin D2, in ragweed-sensitive patients. Similarly, nasal epithelial mast cell numbers are decreased. A characteristic feature of immunotherapy is its ability to inhibit late-phase responses. In the nose it is accompanied by a decrease in eosinophil numbers in lavage during late responses. Characteristic changes in serum immunoglobulins are found, with an initial increase in IgE followed by a blunting of seasonal increases in IgE in pollen-sensitive patients and a gradual decline in allergen-specific IgE levels over several years. This is accompanied by an increase in allergen-specific IgG (blocking antibodies), although neither appear to correlate closely with the clinical response to immunotherapy. One way in which immunotherapy may act is by modifying the T-lymphocyte response to subsequent natural allergen exposure. Studies in peripheral blood and within the target organ have demonstrated a shift in the balance of T-cell subsets away from TH2-type (producing particularly IL-4 and IL-5) in favor of a TH1-type T-lymphocyte response (with the preferential production of IFN-gamma). Studies of the nasal mucosa before and after immunotherapy have demonstrated suppression of the late nasal response and increases in the numbers of cells expressing mRNA for IFN-gamma. It is not clear whether this immune deviation is due to anergy of TH2/TH0 cells or increases in TH0/TH1 T-lymphocyte responses. An alternative may be amplification of suppressor CD8+ T cells, which may have a downregulatory effect. Novel approaches currently being explored include the use of T-cell reactive peptides, which might circumvent the risk of anaphylaxis, and the use of adjuvants such as IL-12 or mycobacterial vaccines to potentiate the effects of allergen in inducing immune deviation.
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PMID:Immunologic changes associated with allergen immunotherapy. 972 54

The therapeutic potential of salbutamol, a beta2-adrenergic agonist, was explored in collagen-induced arthritis. This study was based on a report that salbutamol, by elevating intracellular cAMP, inhibits IL-12 production by macrophages and dendritic cells, thus preventing Th1 development. Ten-week-old male DBA/1 mice were immunized by intradermal injection of type II collagen in CFA. Arthritis developed 15-30 days later and the mice were treated after onset of disease with salbutamol, 200 microgram i.p. After 10 days, the mice were sacrificed, and the hind paws were evaluated histologically. Salbutamol, 200 microgram daily or every other day, had a profound therapeutic effect on the clinical progression of arthritis, as assessed by clinical score and paw thickness. The therapeutic effect was dose dependent. Daily administration of 200 microgram of salbutamol offered the best protection against joint damage, as assessed by histology. In vitro, salbutamol reduced IL-12 and TNF-alpha release by peritoneal macrophages in a dose-dependent manner, as well as TNF release by synovial cells from arthritic mice. Ex vivo, draining lymph node cells of the salbutamol-treated arthritic mice showed a diminished CII-specific IFN-gamma production and proliferation. In vivo, salbutamol specifically blocked mast cell degranulation in joint tissues. In conclusion, salbutamol has important effects on the immunoinflammatory response and a significant therapeutic action in collagen-induced arthritis.
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PMID:The beta2-adrenergic agonist salbutamol is a potent suppressor of established collagen-induced arthritis: mechanisms of action. 1022 75

IL-4-dependent and -independent IgG1 Abs differ in their ability to induce mast cell degranulation as measured by passive cutaneous anaphylaxis (PCA). Mice immunized with OVA or PIII (fraction of Ascaris suum) produced high titers of IgG1 as shown by ELISA and PCA. In contrast, another A. suum fraction, PI, elicited IgG1 Abs with no PCA activity. IgG1 with anaphylactic activity required IL-4, as IgG1 responses to OVA and PIII in IL-4-/- mice gave no PCA. PI-specific IgG1 was IL-4-independent, because no difference was found between the responses of IL-4-/- and IL-4+/+ mice. Significant PCA reactions were elicited, however, with PI-specific IgG1 from IL-12-/- or anti-IFN-gamma Ab-treated mice, although less Ab was measured by ELISA. These results indicate that one type of IgG1 has anaphylactic activity and its synthesis is IL-4-dependent, being inhibited by IL-12 or IFN-gamma; the other lacks this activity and its synthesis is stimulated by IL-12 or IFN-gamma.
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PMID:Cutting edge: mouse IgG1 antibodies comprise two functionally distinct types that are differentially regulated by IL-4 and IL-12. 1049 Sep 48


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