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)

We found that production and release of two functionally antagonistic cytokines, TGF-beta and TNF-alpha, were regulated differently in the mast cell, T cell, and macrophage cell lines RBL-2H3, MLA-144, and U-937, respectively. TGF-beta was produced and released constitutively in all three cell lines. When, however, the cell lines were stimulated with Ag, LPS, or calcium ionophore plus PMA, acceleration of release and some additional production of TGF-beta were apparent. In contrast, TNF-alpha was produced and released only when these lines were stimulated. Although neither the glucocorticoid, dexamethasone, nor the protein kinase C inhibitor, Ro31-7549, suppressed constitutive production or release of TGF-beta, these agents inhibited TNF-alpha production and the inducible component of TGF-beta production noted above. The release of these cytokines, whether constitutive or inducible, was dependent on Golgi-processing as indicated by inhibition with brefeldin A. Therefore, although both types of cytokines were processed by Golgi, only TNF-alpha and the inducible component of TGF-beta production were protein kinase C or steroid-regulated processes. These findings suggested that constitutive and inducible pathways exist for production and release of cytokines and that the inducible pathways can be selectively suppressed by pharmacologic agents.
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PMID:Constitutive and inducible mechanisms for synthesis and release of cytokines in immune cell lines. 889 43

Preconditioning the heart with a short period of ischemia makes it resistant to infarction from a subsequent ischemic insult. We have proposed that preconditioning is triggered by the release of endogenous substances including adenosine which activate protein kinase C through receptormediated cell signaling pathways. However, it has also been proposed that the initial brief ischemia may result in mast cell degranulation without significant myocardial damage, making it less likely that the toxic granule contents could be released to irreversibly damage vulnerable myocardial cells during the subsequent prolonged ischemia. To study the role of mast cells in ischemic preconditioning (PC) isolated rabbit hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 31.9 +/- 2.6% of the risk zone. Preconditioning with 5 min of global ischemia and 10 min of reperfusion reduced infarct size to 5.6 +/- 6.1% (p < 0.01). When disodium cromoglycate (DSCG)(10 microM), a mast cell stabilizer, was infused shortly before the long ischemia it did protect the heart (12.8 +/- 2.9% infarction, p < 0.01 vs control) which supports the mast cell theory. However, a mast cell degranulating agent, compound 48/80 (24 mg/L), added to the perfusate prior to the 30 min ischemic period could not mimic PC (39.7 +/- 5.6% infarction). Mast cell granules are rich in histamine, and the latter was assayed in myocardium by immunoassay as a marker of intact granules. In homogenized left ventricle from normal rabbit hearts and those following a standard PC protocol of 5-min global ischemia/10-min reperfusion, histamine contents were 9.3 +/- 1.4 and 8.9 +/- 1.4 ng/g wet tissue, respectively. Compound 48/80 reduced histamine levels to 2.9 +/- 0.6 ng/g (p < 0.05 vs control). Although baseline histamine contents were 10-fold higher in rats, PC also had no effect, but compound 48/80 reduced content by 91%. Therefore, histamine tissue content and presumably mast cell granules were unaffected by a PC protocol which successfully protected ischemic myocardium, while pharmacological myocardial histamine depletion was not associated with protection. Hence, mast cells do not appear to be important in ischemic preconditioning. Although a mast cell stabilizer such as DSCG can protect ischemic myocardium, it may do so by one of its other properties, e.g., membrane stabilization.
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PMID:Mast cell degranulation does not contribute to ischemic preconditioning in isolated rabbit hearts. 899 31

Tec family protein-tyrosine kinases (PTKs) have been recognized as a distinct subfamily for only a few years. Two of them, Btk and Emt, are tyrosine-phosphorylated and enzymatically activated upon cross-linking of the high-affinity IgE receptor (Fc epsilonRI), suggesting their involvement in mast cell activation. Since Lyn and other Src family PTKs phosphorylate Btk at Tyr-551 and activate the latter kinase, the receptor-associated Lyn seems to activate Btk in mast cells. The Btk kinase activity, on the other hand, is regulated negatively by phosphorylation by protein kinase C (PKC) that is associated with Btk via Btk's pleckstrin homology (PH) domain. PH domains also bind to phospholipids and the beta subunit of heterotrimeric GTP-binding proteins. Therefore, it has been hypothesized that PH domains play roles in membrane localization.
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PMID:Tec family protein-tyrosine kinases and pleckstrin homology domains in mast cells. 905 64

The SH2 domain-containing inositol-polyphosphate 5-phosphatase, SHIP, associates with FcgammaRIIB and negatively regulates both B-cell and mast cell function. We report here that SHIP was tyrosine-phosphorylated after high affinity IgE receptor (FcepsilonRI) aggregation in rat basophilic leukemia RBL-2H3 cells. The tyrosine phosphorylation of SHIP was an early event after receptor aggregation and was present in cells deficient in the protein-tyrosine kinase Syk. Furthermore it was not secondary to the increase of intracellular calcium or the activation of protein kinase C. SHIP was precipitated by immobilized phosphorylated synthetic peptides based on the immunoreceptor tyrosine-based activation motif (ITAM) of the beta but not the gamma subunit of the high affinity IgE receptor. Tyrosine phosphorylation of SHIP and its association with the tyrosine-phosphorylated beta subunit of FcepsilonRI could play an important role in down-regulating receptor-mediated signal transduction in mast cells. Thus, whereas the activation molecule Syk associates with the gamma subunit ITAM, the beta subunit ITAM binds the negative signaling molecule SHIP. Therefore, unlike B cells where the antigen receptor and coreceptors such as FcgammaRIIB or CD22 each recruits molecules with opposite effects, the FcepsilonRI contains subunits which recruit molecules that activate and inhibit signal transduction.
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PMID:The negative signaling molecule SH2 domain-containing inositol-polyphosphate 5-phosphatase (SHIP) binds to the tyrosine-phosphorylated beta subunit of the high affinity IgE receptor. 915 64

Carbachol and 5'-(N-ethylcarboxamido)-adenosine (NECA), stimulants of G protein-coupled receptors, induce MAP kinase activation in the muscarinic ml receptor-transfected mast cell line, RBL-2H3 (ml) cells. The phospholipase C inhibitor neomycin and the phosphatidate phosphohydrolase inhibitor propranolol augmented MAP kinase activation induced by carbachol and NECA without affecting the antigen-induced MAP kinase activation. Furthermore, the duration of MAP kinase activation induced by carbachol or NECA was also prolonged by neomycin and propranolol. The specific protein kinase C inhibitor Ro 31-8425 enhanced the carbachol- or NECA-induced MAP kinase activation. These findings suggest that the MAP kinase activation mediated by the G protein-coupled receptors is negatively regulated by diacylglycerol and activated protein kinase C(s).
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PMID:Negative regulation of MAP kinase by diacylglycerol-dependent mechanisms via G protein-coupled receptors in rat basophilic RBL-2H3 (ml) cells. 921 34

1. Inhalation of vanadium compounds, particularly vanadate, is a cause of occupational bronchial asthma. We have now studied the action of vanadate on human isolated bronchus. Vanadate (0.1 microM-3 mM) produced concentration-dependent, well-sustained contraction. Its -logEC50 was 3.74 +/- 0.05 (mean +/- s.e.mean) and its maximal effect was equivalent to 97.5 +/- 4.2% of the response to acetylcholine (ACh, 1 mM). 2. Vanadate (200 microM)-induced contraction of human bronchus was epithelium-independent and was not inhibited by indomethacin (2.8 microM), zileuton (10 microM), a mixture of atropine, mepyramine and phentolamine (each at 1 microM), or by mast cell degranulation with compound 48/80. 3. Vanadate (200 microM)-induced contraction was unaltered by tissue exposure to verapamil or nifedipine (each 1 microM) or to a Ca2+-free, EGTA (0.1 mM)-containing physiological salt solution (PSS). However, tissue incubation with ryanodine (10 microM) in Ca2+-free, EGTA (0.1 mM)-containing PSS reduced vanadate-induced contraction. A series of vanadate challenges was made in tissues exposed to Ca2+-free EGTA (0.1 mM)-containing PSS with the object of depleting intracellular Ca2+ stores. In such tissues cyclopiazonic acid (CPA; 10 microM) prevented Ca2+-induced recovery of vanadate-induced contraction. 4. Tissue incubation in K+-rich (80 mM) PSS, K+-free PSS, or PSS containing ouabain (10 microM) did not alter vanadate (200 microM)-induced contraction. Ouabain (10 microM) abolished the K+-induced relaxation of human bronchus bathed in K+-free PSS. This action was not shared by vanadate (200 microM). The tissue content of Na+ was increased and the tissue content of K+ was decreased by ouabain (10 microM). In contrast, vanadate (200 microM) did not alter the tissue content of these ions. Tissue incubation in a Na+-deficient (25 mM) PSS or in PSS containing amiloride (0.1 mM) markedly inhibited the spasmogenic effect of vanadate (200 microM). 5. Vanadate (200 microM)-induced contractions were markedly reduced by tissue treatment with each of the protein kinase C (PKC) inhibitors H-7 (10 microM), staurosporine (1 microM) and calphostin C (1 microM). Genistein (100 microM), an inhibitor of protein tyrosine kinase, also reduced the response to vanadate. 6 Vanadate (0.1-3 mM) and ACh (1 microM- 3 mM) each increased inositol phosphate accumulation in bronchus. Such responses were unaffected by a Ca2+-free medium either alone or in combination with ryanodine (10 microM). 7. In human cultured tracheal smooth muscle cells, histamine (100 microM) and vanadate (200 microM) each produced a transient increase in intracellular Ca2+ concentration ([Ca2+]i). 8. Intracellular microelectrode recording showed that the contractile effect of vanadate (200 microM) in human bronchus was associated with cellular depolarization. 9. It is concluded that vanadate acts directly on human bronchial smooth muscle, promoting the release of Ca2+ from an intracellular store. The Ca2+ release mechanism involves both the production of inositol phosphate second messengers and inhibition of Ca-ATPase. The activation of PKC plays an important role in mediating vanadate-induced contraction at values of [Ca2+]i that are close to basal.
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PMID:The spasmogenic effects of vanadate in human isolated bronchus. 925 12

The rat basophilic leukemic (RBL-2H3) cell line was stably transfected with the endogenously expressed Ca2+-dependent protein kinase C-alpha (PKC-alpha) and -betaI and the Ca2+-independent delta and epsilon isoforms to study their functional roles. In addition, the Ca2+-independent PKC-eta was expressed. All transfected PKC isoforms translocated to the membrane-containing fraction in response to aggregation of the IgE-sensitized high affinity receptor for IgE (Fc epsilonRI) with the Ag dinitrophenyl(25)-BSA. All PKC transfectants, except PKC-eta, showed increased proliferative responses, and aggregation of Fc epsilonRI further enhanced the rate of proliferation. The PKC transfectants also showed increased phosphoinositide hydrolysis in response to Ag aggregation of receptors. No marked differences in the Ca2+ responses of the transfectants to Ag or thapsigargin were observed. Overexpression of PKC-alpha or -epsilon specifically inhibited receptor-dependent cytosolic phospholipase A2 (cPLA2) activity, whereas this activity was enhanced in the PKC-betaI transfectant. Analysis of the secretory response revealed that overexpression of PKC-betaI and -eta significantly enhanced secretion. A broad spectrum of cytokine mRNAs was detected in all transfectants, and overexpression of PKC-betaI significantly enhanced the receptor-dependent production of IL-2 and IL-6 mRNA. These studies identify PKC-alpha and -epsilon as negative regulators of cPLA2 activity and demonstrate the importance of PKC-beta as a positive modulator of secretion, cPLA2 activity, and cytokine production in this mast cell line.
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PMID:Functional effects of overexpression of protein kinase C-alpha, -beta, -delta, -epsilon, and -eta in the mast cell line RBL-2H3. 930 Jun 81

The mast cell plays a pivotal role in initiating allergic inflammation by secreting several cytokines including TNF-alpha, in addition to granule mediators such as histamine. Anti-allergic drugs including azelastine prevent immediate-type hypersensitivity by inhibiting mast cell degranulation, as well as blocking histamine H1 receptors. However, their effects on cytokine release from mast cells remain unknown. In a rat mast RBL-2H3 cell line, azelastine inhibited Ag- and ionomycin-induced TNF-alpha release with IC50 values of 25.7 +/- 3.4 microM and 1.66 +/- 0.45 microM, respectively. These effects were observed at lower concentrations than needed for the inhibition of degranulation. In Ag-stimulated cells, azelastine also inhibited TNF-alpha mRNA expression, TNF-alpha protein synthesis and release, and, possibly related to these effects, Ca2+ influx. In ionomycin-stimulated cells, however, azelastine inhibited TNF-alpha release to a greater extent than mRNA expression/protein synthesis and Ca2+ influx, suggesting that azelastine inhibits the release process more potently than transcription or production of TNF-alpha by interfering with a signal other than Ca2+. Azelastine added 1 h after ionomycin stimulation also immediately blocked subsequent release of TNF-alpha, which had been produced in the cells, without affecting Ca2+ influx. Pretreatment with 1 microM azelastine inhibited ionomycin-induced, but not Ag-induced, protein kinase C translocation to the membranes. These results suggest that the release process of TNF-alpha in mast cells is regulated by a mechanism distinct from that of degranulation, and that in Ca2+-ionophore-stimulated cells, it is also different from that of transcription/production, and possibly involves protein kinase C activation.
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PMID:Suppression of TNF-alpha secretion by azelastine in a rat mast (RBL-2H3) cell line: evidence for differential regulation of TNF-alpha release, transcription, and degranulation. 930 Jul 17

CD43 has been shown to be involved in the regulation of cellular adhesion and activation of leukocytes, but its functional significance for mast cell biology has been poorly defined. We demonstrate here that mAb engagement of surface CD43 on human leukemic (HMC-1) mast cells initiates a signaling cascade which involves protein kinase C, while tyrosine kinases appear to play a minor role, as evidenced by effects of different kinase inhibitors on homotypic aggregation induced via CD43. Furthermore, administration of an activating anti-CD43 mAb is shown to induce and promote TNF-alpha- and to enhance IL-8-secretion from HMC-1 cells, but it does not initiate histamine, tryptase, or LTC4 release, suggesting that the intracellular pathways leading to aggregation and release of certain mast cell mediators are differentially regulated. Additionally, engagement of CD43 on HMC-1 cells leads to down-regulation of CD43 surface expression, implying that CD43 may be potentially involved in its own regulation.
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PMID:Signal transduction via CD43 (leukosialin, sialophorin) and associated biological effects in human mast cell line (HMC-1). 947 99

Disodium cromoglycate (cromolyn) is a well documented inhibitor of immunologically-induced histamine release from rat peritoneal mast cells and has been shown to stimulate the phosphorylation of a mast cell protein of apparent molecular mass 78,000 Da (78 kDa), an event which may be involved in terminating secretion. Here we aimed to determine the role of the ubiquitous enzyme, protein kinase C, in the phosphorylating activity of cromolyn by examining the effects of phorbol esters (activators of protein kinase C) on protein phosphorylation in [32P]orthophosphate loaded rat peritoneal mast cells. Protein kinase C-activating phorbol esters such as 12-O-tetradecanoyl phorbol-13-acetate (TPA) and 4beta-phorbol 12,13-dibutyrate (PdBu) were found to potently inhibit cromolyn-induced phosphorylation when added to mast cells simultaneously with cromolyn (IC50 22 and 79 nM respectively). 4Alpha-phorbol 12,13-didecanoate (PdD), a phorbol ester which does not activate protein kinase C, had no effect on cromolyn-induced phosphorylation. Addition of TPA to mast cells previously exposed to cromolyn for 60 sec (i.e. when 78-kDa protein phosphorylation is maximal) also caused a very rapid dephosphorylation of the 78-kDa protein. Phosphorylation of the 78-kDa protein can also be induced by dibutyryl cyclic GMP and this action was similarly inhibited by TPA and PdBu. Cromolyn inhibited secretion induced by anti-IgE, but not by TPA, and thus inhibition of secretion by cromolyn is further correlated to its phosphorylation of the 78-kDa protein. The data suggest that the inhibitory action of cromolyn on mast cell secretion and phosphorylation of the 78-kDa protein are not mediated through a phorbol ester-sensitive protein kinase C, but more likely that such an enzyme could be involved in regulating dephosphorylation of the 78-kDa protein. Further explanations for this novel dephosphorylating activity of phorbol esters are discussed.
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PMID:Inhibition of cromolyn-induced phosphorylation of a 78-kDa protein by phorbol esters in rat peritoneal mast cells. 951 69


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