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)

We studied the effects of representative endocrine-disrupting chemicals on beta-hexosaminidase release from mast cells and their putative neurosteroid receptor involvement. Some endocrine-disrupting chemicals, such as amitrol, benzophenon, bisphenol A, pentachlorophenol, and tetrabromophenol A did not cause hexosaminidase release from RBL-2H3 cells, but they blocked the release by dehydroepiandrosterone sulfate, a representative neurosteroid agonist. On the contrary, atrazine, which is a widely used herbicide, caused a rapid and concentration-dependent degranulation in the range between 10 nM and 1 microM in RBL-2H3 and peritoneal mast cells. Atrazine-induced degranulation was also evaluated by Alexa 488-annexin V binding to the phosphatidylserine, which is externalized during degranulation, and these actions were blocked by BSA-conjugated (membrane-impermeable) progesterone (PROG-BSA). The atrazine-induced beta-hexosaminidase release was characterized by various inhibitors including antisense-oligodeoxynucleotide for Galpha(q/11), pertussis toxin, phospholipase C inhibitor U-73122, inositol 1,4,5-triphosphate receptor inhibitor xestospongin C and Ca(2+) channel blocker lanthanum chloride. These analyses revealed that the degranulation is mediated by putative metabotropic neurosteroid receptor, G(q/11), phospholipase C and Ca(2+) mobilization from intracellular stores. Having documented progesterone receptor-modulation of atrazine-induced mast cell degranulation in vitro, this response was evaluated in mice. Atrazine caused pain responses when injected in the foot pads of mice, and they were antagonized by local administration of PROG-BSA or diphenhydramine. Atrazine also caused PROG-BSA-reversible plasma extravasation. All these findings strongly suggest that herbicide atrazine exerts inflammatory activity through activation of putative G(q/11)-coupled neurosteroid receptor and phospholipase C.
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PMID:Endocrine disrupting chemical atrazine causes degranulation through Gq/11 protein-coupled neurosteroid receptor in mast cells. 1638 60

We established a new and facile model to investigate allergic mechanism and assess the effect of antiallergic compounds. Male Wistar rats were actively or passively sensitized. Active sensitization was performed by injection of both dinitrophenylated-ovalbumin (DNP-OA) and Bordetella pertussis. Nine days later, DNP-OA was injected into the right hind footpad. This antigen challenge induced a biphasic footpad swelling that consisted of an early-phase (EPR) and a late-phase response (LPR). In rats passively sensitized with rat anti-DNP-OA serum, DNP-OA induced only EPR. The EPR was suppressed by disodium cromoglycate, a mast cell stabilizer, but not by cyclosporin A, an immunosuppressant, while the LPR was suppressed by cyclosporin A. Furthermore, to investigate these two allergic responses determined by the interactions between the hapten and the carrier proteins, two distinct haptenated antigens were created. DNP-Ascaris (DNP-As) induced a marked EPR and LPR in DNP-As-sensitized rats. However, DNP-As induced only EPR in DNP-OA-sensitized rats, indicating that the usage of the same carrier protein in both sensitization and challenge was necessary for induction of LPR. These data suggest that this actively sensitization model in which EPR and LPR are functionally distinguishable should be useful for evaluating the efficacy of antiallergic compounds.
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PMID:A late cutaneous response in actively sensitized rats: a new method for evaluating the efficacy of antiallergic drugs. 1689 62

Toll-like receptors (TLRs) expressed in mast cells play important roles in orchestrating host defence against bacterial pathogens. Previous studies demonstrated that TLR2 agonist tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3Cys) stimulates both degranulation and cytokine production in human mast cells but only induces cytokine production in murine mast cells. To determine the molecular basis for this difference, we utilized a human mast cell line LAD 2, murine lung and bone marrow-derived mast cells (MLMC and BMMC). We found that Pam3Cys caused a sustained Ca2+ mobilization and degranulation in LAD 2 mast cells but not in MLMC or BMMC. Despite these differences, Pam3Cys stimulated equivalent chemokine CCL2 generation in all mast cell types tested. Cyclosporin A (CsA), an inhibitor of Ca2+/calcineurin-mediated nuclear factor of activated T cells (NFAT) activation, blocked chemokine production in LAD 2 but not in MLMC or BMMC. In contrast, inhibitors of nuclear factor kappa B (NF-kappaB) completely blocked CCL2 production in MLMC and BMMC but not in LAD 2 mast cells. Pertussis toxin and U0126, which, respectively, inhibit Galphai, extracellular signal-regulated kinase (ERK) phosphorylation substantially inhibited Pam3Cys-induced CCL2 generation in LAD 2 mast cells but had little or no effect on chemokine generation in MLMC and BMMC. These findings suggest that TLR2 activation in human LAD 2 mast cells and MLMC/BMMC promotes the release of different classes of mediators via distinct signalling pathways that depend on Ca2+ mobilization and G protein usage.
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PMID:Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll-like receptor function in human and murine mast cells. 1706 16

Antimicrobial peptides human beta-defensins (hBD) are mainly produced by epithelia of several organs including skin, and participate in innate immunity by killing invading pathogens. Besides their microbicidal activities, hBD activate several inflammatory and immune cells. Since hBD are generated by tissues where mast cells are present, we hypothesized that these peptides could activate mast cells. In this study, we demonstrated that both hBD-3 and hBD-4 induced mast cell degranulation, prostaglandin D2 production, intracellular Ca2+ mobilization and chemotaxis. Furthermore, hBD-3- and hBD-4-induced activation of mast cells was suppressed by pertussis toxin and U-73122, inhibitors for G protein and phospholipase C, respectively. We further revealed that hBD-3 and hBD-4 increased vascular permeability in the skin, which was dependent on the presence of mast cells, because hBD-3 and hBD-4 failed to enhance vascular permeability in mast cell-deficient Ws/Ws rats. We also demonstrated that hBD-3 and hBD-4 induced phosphorylation of MAPK p38 and ERK1/2, which were further required for hBD-mediated mast cell activation, as evidenced by the inhibitory effects of p38 and ERK1/2 inhibitors on mast cell degranulation. Together, these findings suggest the key role of hBD in inflammatory responses by recruiting and activating mast cells, and increasing vascular permeability.
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PMID:Antimicrobial peptides human beta-defensin (hBD)-3 and hBD-4 activate mast cells and increase skin vascular permeability. 1723 Apr 40

Antigen/IgE-mediated mast cell activation via FcvarepsilonRI can be markedly enhanced by the activation of other receptors expressed on mast cells and these receptors may thus contribute to the allergic response in vivo. One such receptor family is the G protein-coupled receptors (GPCRs). Although the signaling cascade linking FcvarepsilonRI aggregation to mast cell activation has been extensively investigated, the mechanisms by which GPCRs amplify this response are relatively unknown. To investigate this, we utilized prostaglandin (PG)E2 based on initial studies demonstrating its greater ability to augment antigen-mediated degranulation in mouse mast cells than other GPCR agonists examined. This enhancement, and the ability of PGE2 to amplify antigen-induced calcium mobilization, was independent of phosphoinositide 3-kinase but was linked to a pertussis toxin-sensitive synergistic translocation to the membrane of phospholipase (PL)Cgamma and PLCbeta and to an enhancement of PLCgamma phosphorylation. This "trans-synergistic" activation of PLCbeta and gamma, in turn, enhanced production of inositol 1,4,5-trisphosphate, store-operated calcium entry, and activation of protein kinase C (PKC) (alpha and beta). These responses were critical for the promotion of degranulation. This is the first report of synergistic activation between PLCgamma and PLCbeta that permits reinforcement of signals for degranulation in mast cells.
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PMID:Synergistic activation of phospholipases Cgamma and Cbeta: a novel mechanism for PI3K-independent enhancement of FcepsilonRI-induced mast cell mediator release. 1820 1

Accumulating evidence has indicated that mast cells can modulate a wide variety of immune responses. Migration and adhesion play a critical role in regulation of tissue mast cell function, in particular, under inflammatory conditions. We previously demonstrated that prostaglandin (PG) E(2) stimulates adhesion of a mouse mastocytoma cell line, P-815, to the Arg-Gly-Asp (RGD)-enriched matrix through cooperation between two PGE(2) receptor subtypes: EP3 and EP4 (Hatae N, Kita A, Tanaka S, Sugimoto Y, Ichikawa A. J Biol Chem 278: 17977-17981, 2003). We here investigated PGE(2)-induced adhesion of IL-3-dependent bone marrow-derived cultured mast cells (BMMCs). In contrast to the elevated cAMP-dependent adhesion of P-815 cells, EP3-mediated Ca(2+) mobilization plays a pivotal role in PGE(2)-induced adhesion of BMMCs. Adhesion and Ca(2+) mobilization induced by PGE(2) were abolished in the Ptger3(-/-) BMMCs and were significantly suppressed by treatment with pertussis toxin, a phospholipase C inhibitor, U-73122, and a store-operated Ca(2+) channel inhibitor, SKF 36965, indicating the involvement of G(i)-mediated Ca(2+) influx. We then investigated PGE(2)-induced adhesion of peritoneal mast cells to the RGD-enriched matrix. EP3 subtype was found to be the dominant PGE receptor that expresses in mouse peritoneal mast cells. PGE(2) induced adhesion of the peritoneal mast cells of the Ptger3(+/+) mice, but not that of the Ptger3(-/-) mice. In rat peritoneal mast cells, PGE(2) or an EP3 agonist stimulated both Ca(2+) mobilization and adhesion to the RGD-enriched matrix. These results suggested that the EP3 subtype plays a pivotal role in PGE(2)-induced adhesion of murine mast cells to the RGD-enriched matrix through Ca(2+) mobilization.
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PMID:Essential role of EP3 subtype in prostaglandin E2-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix. 1881 28

Induction of T helper 1 (Th1) to Th2 deviation through administration of self- or altered self-peptides holds promise for treatment of autoimmunity. However, administration of self-peptides in models of autoimmunity can result in anaphylactic reactions. Although both IgE and IgG1 antibodies might be involved in the development of anaphylaxis to myelin peptides in experimental autoimmune encephalomyelitis in mice, the effector cells and molecules involved are not fully understood. Here we show that systemic anaphylaxis to the self-antigen myelin oligodendrocyte glycoprotein (MOG) 35-55 can occur in mice lacking mast cells (Kit(W)/Kit(W-v) mice) or histamine (histidine decarboxylase-deficient mice), but is prevented in mice lacking IL-4. Treatment of mice with CV6209, a platelet-activating factor antagonist, slightly reduced the incidence of anaphylaxis to self-MOG35-55 in this model, but more effectively protected mice against anaphylaxis to this peptide when self-MOG35-55 was administered in a different immunization protocol that omitted the use of Bordetella pertussis toxin as an adjuvant at the time of immunization. Thus, anaphylactic reactions to self-MOG can occur in the absence of mast cells or histamine, key elements of the classical IgE-, mast cell-, and histamine-dependent pathway of anaphylaxis.
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PMID:Anaphylaxis to a self-peptide in the absence of mast cells or histamine. 1918 9

Mast cells play pivotal roles in allergic and inflammatory processes via distinct activation pathways. Mucosal and serosal mast cells are activated by the IgE/FcepsilonRI pathway, while only serosal mast cells are activated by basic secretagogues. We show that CD47 receptors are expressed on rat peritoneal mast cells. 4N1K, a peptide agonist of CD47, rapidly caused exocytosis. Such exocytosis required increased intracellular calcium and was inhibited by pertussis toxin and an antibody against the betagamma dimer of a G(i) protein. Cooperation with integrins and glycosylphosphatidylinositol-anchored proteins was necessary, since anti-integrin antibodies and pretreatment with phosphatidylinositol-phospholipase C reduced exocytosis. Depletion of membrane cholesterol inhibited exocytosis and decreased CD47 in lipid rafts, consistent with a CD47/integrin/G(i) protein complex being located in rafts. An anti-CD47 antibody inhibited exocytosis induced by 4N1K and by mastoparan and spermine, suggesting that basic secretagogues might target CD47. We propose that 4N1K-stimulated mast cell exocytosis involves a CD47/integrin/G(i) protein complex.
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PMID:Activation of CD47 receptors causes histamine secretion from mast cells. 1920 21

Phosphatidylinositol 3-kinase (PI3K) has been recognized as an important downstream effector of high-affinity receptor for IgE (FcepsilonRI) signaling in mast cells, but little is known about the isoform specificity of PI3Ks on the FcepsilonRI-mediated migration toward the antigen (Ag). In the present study, we explored the role of PI3Kgamma on mast cell migration. The treatment of bone marrow-derived mast cells (BMMCs) with a PI3Kgamma inhibitor, AS605240, significantly repressed FcepsilonRI-induced degranulation and migration. The culture supernatants of wild-type mast cells stimulated with IgE and Ag attracted FcepsilonRIbeta(-/-) mast cells which did not express FcepsilonRI on their cell surface, indicating that the migration appears to be dependent on an autocrine/paracrine secretion of soluble factors from the mast cells. Adenosine, which is produced by mast cells, showed a strong activity to attract mast cells. Pertussis toxin (PTX) significantly inhibited the migration toward both the supernatant and adenosine. The supernatant from mast cells pretreated with wortmannin (Wort) and stimulated with IgE and Ag still exhibited the activity as chemoattractant, while the BMMCs pretreated with Wort did not migrate toward the supernatant. Although PTX significantly reduced the activation of AKT/PKB and migration, PTX had no effects on degranulation. These results suggest that PI3Kgamma activation through PTX-sensitive G-protein-coupled receptor as a secondary response of FcepsilonRI cross-linking regulates FcepsilonRI-mediated mast cell migration toward the Ag, while simultaneously activated PI3Kgamma through a PTX-insensitive pathway might have an effect on degranulation.
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PMID:PI3Kgamma differentially regulates FcepsilonRI-mediated degranulation and migration of mast cells by and toward antigen. 1949 8

Mast cells are found in the brain, where they contribute to immune responses. They have been implicated in multiple sclerosis, but their potential role in Alzheimers disease (AD), another inflammatory disease of the central nervous system, remains elusive. In the present study, we examined mast cell responses to amyloid beta (Abeta) peptides 1-40 and 1-42, the major components of the Alzheimer amyloid plaques. Rat peritoneal mast cells were used as experimental model for human brain serosal mast cells. Fibrillar Abeta1-40 and Ami1-42 peptides induced concentration-dependent exocytosis, as assessed by measurement of histamine secretion; exocytosis was reduced by pre-treatment with pertussis toxin and with antibodies against the CD47 receptor and the beta1-integrin subunit. Fibrillar Abeta1-40 and Abeta1- 42 peptides coated on heat-inactivated yeast particles and soluble fibrillar Abeta1-40 and Abeta1-42 peptides were also recognized and phagocyted by mast cells. Uptake of the peptides was decreased in the presence of 4N1, a peptide agonist of the CD47 receptor, but remained unchanged in the presence of 4NGG, a peptide derived from 4N1 which does not bind to CD47. Non-fibrillar forms of Abeta1-40 and 1-42 peptides were unable to elicit mast cell responses. These results show that fibrillar Abeta peptides can trigger mast cells and elicit exocytosis and phagocytosis. The Abeta-induced activation of mast cells operates through a CD47/beta1-integrin membrane complex coupled with Gi-protein. The present data support the hypothesis that mast cells, similarly to microglial cells, could play a major role in AD pathogenesis.
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PMID:Amyloid beta peptides trigger CD47-dependent mast cell secretory and phagocytic responses. 1950 77


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