Potentiation Of Histamine Release Research Articles

Protein kinase C regulation of the receptor-coupled calcium signal in histamine-secreting rat basophilic leukaemia cells

It has been proposed that protein kinase C mediates cellular responses evoked by external stimuli, leading to alterations in internal free calcium concentrations. We have shown previously that histamine-secreting rat basophilic leukaemia cells (RBL-2H3), which degranulate on aggregation of the receptors for immunoglobulin IgE, contain a Ca2+- and phospholipid-dependent protein kinase (kinase C). The partially purified enzyme is activated directly by the tumour-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In intact RBL cells, TPA potentiates histamine release induced by the Ca2+-ionophore A23187 (similar to the synergy reported for platelets, neutrophils and rat peritoneal mast cells). Although TPA at concentrations below 15 nM synergizes with the antigen, higher TPA concentrations inhibit secretion. This selective inhibition suggested that kinase C is involved in both the activation and termination of the secretory process. To examine this possibility, we have determined the effect of TPA on changes in free cytosolic Ca2+ concentration during antigen-induced release. We report here that TPA completely blocks the increase in Ca2+ concentration induced by antigen. Our results strongly suggest that protein kinase C is involved in the regulation of receptor-dependent Ca2+ signalling.

Adenosine inhibits and potentiates IgE-dependent histamine release from human lung mast cells by an A 2-purinoceptor mediated mechanism

Adenosine, at physiological concentrations, may modulate histamine release from mechanically dispersed human lung mast cells. Addition of adenosine to the dispersed mast cells at times up to 5 min before immunological challenge with anti-human IgE inhibited histamine release. When added after this time adenosine caused a small potentiation of immunological histamine release, maximum potentiation occurring with addition of adenosine 5 min after challenge, coincidental with the end of the rapid phase of histamine release. Both inhibition and potentiation of histamine release were more pronounced with low levels of immunological challenge. Theophylline, 8-phenyltheophylline, dipyridamole and analogues of adenosine were used to determine the site of action of adenosine on mast cell mediator release. Theophylline and 8-phenyltheophylline displaced the concentration-response lines for both inhibition and potentiation of mediator release by adenosine to the right whilst dipyridamole, 1 μM, was without significant effect. This suggests that both effects result from interaction of adenosine with cell surface receptors. This was confirmed by demonstrating that the P-site agonist 2',5'-dideoxyadenosine produced only inhibition of histamine release, an effect which was inhibited by dipyridamole but not by theophylline. The rank potency order of adenosine analogues, NECA ⪢ adenosine ⩾ L - PIA ⩾ D in both inhibiting and potentiating immunological histamine release suggests that both effects are mediated through activation of cell surface A 2-purinoceptors. Since adenosine is released into the circulation of asthmatic subjects following bronchial provocation with antigen, causes bronchoconstriction and has the ability to modulate mast cell histamine release, this nucleoside should be considered as an additional inflammatory mediator of allergic reactions.

Sodium-potassium ATPase inhibition potentiates compound 48/80-induced histamine secretion from mast cells.

The effect of ouabain on the histamine secretion induced by compound 48/80 has been studied using rat peritoneal mast cells. Ouabain did not modify histamine release in the presence of millimolar concentrations of extracellular calcium. However, when mast cells were previously washed with a calcium-free buffer, ouabain strongly potentiated histamine release elicited by compound 48/80. The full potentiation of mast cell secretion by ouabain required 30 min preincubation before adding compound 48/80. It was inhibited by lanthanum and EGTA. Potassium deprivation mimicked the effect of ouabain. A 30 min preincubation time without potassium was also required. Potassium concentrations below 2.7 mM increased the effect of ouabain whereas higher potassium concentrations reversed this effect. The potentiation of compound 48/80-induced histamine release by ouabain or potassium deprivation was not immediately reversed by washing away ouabain or by adding potassium, respectively. The data confirm that sodium-potassium ATPase is involved, through a calcium-dependent process, in the regulation of histamine release from mast cells.

Anomalous effects of disodium cromoglycate. A study on two secretory systems.

The effects of disodium cromoglycate (DSCG) on in vitro histamine release from peritoneal and pleural mast cells, and a possible interference with adrenergic mechanisms was studied. Parallel to this study, the effects of DSCG on the well-established adrenoceptor-mediated amylase release from parotid glands were investigated. It was found that DSCG in low concentrations potentiates histamine release from peritoneal mast cells. Further more, this potentiation is enhanced by alpha-adrenoceptor blockade and diminished by beta-adrenoceptor antagonists. Histamine release from pleural mast cells is affected inversely to peritoneal cells, that is, the secretion is inhibited by DSCG at a high concentration but not at a low one. The inhibition is unaffected by alpha-blockers but totally abolished by the beta-antagonist propranolol. The amylase release induced by norepinephrine, mediated via beta1-adrenoceptor, is depressed by DSCG. The beta-antagonist-sensitive amylase release induced by phentolamine is also inhibited by DSCG. Finally, DSCG alone induces amylase release from the parotid gland. These results would seem to indicate that DSCG exerts some alpha-adrenoceptor activity. However, it is not possible, at present, to state whether this activity is of agonistic nature. DSCG has effects which with respect to pattern, correspond well to the action of beta-adrenoceptor agonists.

The role of plasma membrane Ca++-Mg++ activated adenosine triphosphatase of rat mast cells on histamine release.

The role of a Ca++-MG++ activated ATPase, demonstrated on the outer surface of rat peritoneal mast cells, on histamine release induced by antigen (anaphylactic reaction), compound 48/80 and ionophore A23187 has been studied. A high level of the enzyme activity is retained at the optimal pH for histamine release induced by the three releasing agents. The effect of fourteen inhibitors of ATPase has been studied, viz. quinidine, fluoride, platinum salt, suramin, ethacrynic acid, ethyl alcohol, N-ethylmaleimide, Mn++, Ni++, ADP, AMP and the flavones: kaempferol, quercetin, morin. All the inhibitors, which caused varying degrees of inhibition of ATPase, also inhibited histamine release. The inhibition of the enzyme was competitive with ADP, AMP, ethacrynic acid, suramin and morin and non-competitive with the others. The degree of inhibition of ATPase and of histamine release tended to be similar with six inhibitors. With the others the extent of the inhibition of the release and of the enzyme varied. But a marked inhibition of the enzyme was always associated with a pronounced inhibition of histamine release. ATP in lower concentrations (10-20 microM) has been shown to potentiate histamine release induced by all the three releasers, possibly through its utilization by plasma membrane ATPase. The observations agree with the hypothesis that plasma membrane ATPase participates in the histamine release process.

Potentiation of histamine release by sodium cromoglycate

Human lung slices passively sensitized with allergic serum released histamine when incubated with specific antigen and anti-IgE but anti-IgG had no effect. Sodium cromoglycate (SCG) inhibited antigen induced histamine release but the dose-response curve was bell-shaped. Inhibition of anti-IgE induced release was linearly related to dose, whereas that induced by anti-IgG was potentiated by increasing doses of SCG. After sensitization with allergic serum in which IgE had been inactivated by heating, specific antigen released little or no histamine but this was potentiated by SCG. It is concluded that SCG inhibits IgE mediated but potentiates IgG mediated allregic reactions thus explaining its characteristic dose-response curve in vitro .

Modulation of antigen-induced histamine release from bovine granulocytes by several anti-allergic agents.

Sensitised bovine granulocytes release histamine when exposed to antigen. Several anti-allergic agents, some previously shown to be active in cattle, were tested to investigate their modulation of this histamine release process. Diethylcarbamazine citrate potentiated release at low concentrations and inhibited at high concentrations. Sodium meclofenamate and PR-D-92-EA were potent inhibitors. Acetylsalicylic acid and ICI 74,917 inhibited at high concentrations. Disodium cromoglycate was relatively ineffective, although it potentiated histamine release at low concentrations.

The action of local anaesthetics on histamine release

The effect of the local anaesthetics lidocaine, procaine and tetracaine on compound 48/80-induced histamine release from isolated rat mast cells has been investigated. They inhibited histamine release in a dose-dependent manner; at a concentration of 20 mM there was almost total inhibition of histamine release by lidocaine and about 75% inhibition by procaine. Tetracaine exerted a biphasic effect: at concentrations below 1 mM it inhibited, but at concentrations above 1 mM it potentiated histamine release. The inhibitory effect of lidocaine on compound 48/80-evoked histamine release was dependent upon the time of preincubation of mast cells with this anaesthetic and it persisted after washing the cells and resuspension in a lidocaine-free medium. An increase of calcium ions antagonized the inhibitory action of lidocaine. These results can be explained by (1) blockade of membrane receptors for calcium binding which leads to a decrease in intracellular calcium concentration and (2) increase of cellular cyclic AMP content which subsequently inhibits the releasing process.

Cyclic AMP independent inhibition by papaverine of histamine release induced by compound 48/80

Compound 48/80-induced histamine release from isolated rat peritoneal mast cells was inhibited in a dose-dependent manner by papaverine ( ic 50 approx 20 μM). This effect of papaverine was not influenced by PGE 1 (14–140 μM), even though PGE 1 markedly increased must cell cAMP levels. Papaverine (0.5 mM) completely inhibited histamine release without causing any change in cAMP levels. Theophylline (0.1 and 0.5 mM) potentiated histamine release induced by submaximal concentrations of compound 48/80, while cAMP levels were increased. IBM X was as potent as papaverine in causing inhibition of mast cell phosphodiesterase. IBM X (0.14–0.7 mM) had no effect on histamine release but caused a 6–20 fold increase in mast cell cyclic AMP. Papaverine inhibition of histamine release was gradual at the onset and was parallelled by a depletion of mast cell ATP content. The inhibition of 48/80-induced histamine release and depletion of mast cell ATP levels was reversed by glucose. It is concluded that papaverine induced inhibition of 48/80-induced histamine release is independent of cAMP, is unrelated to phosphodiesterase inhibition but is dependent upon inhibition of energy production.

Histamine release from human leukocytes: Modulation by cadmium ion

The effect of cadmium on histamine release was studied in relation to the role of calcium. The antigenic histamine release from peripheral leukocytes of ragweed-sensitive patients was inhibited in the presence of cadmium (>10 −5 M). Spontaneous histamine release was not affected by cadmium except for an enhancement observed in high concentrations (≥10 −3 M). Cadmium did not seem to affect the first stage of histamine release but to act mainly on the calcium-dependent second stage. Increasing the level of calcium in the medium could antagonize the inhibitory effect of cadmium. The effect of cadmium could be totally abolished by deuterium oxide and partially by dibutyryl cyclic adenosine monophosphate (AMP) in certain concentrations. These results would indicate that: (1) cadmium acts as an antagonist of calcium and can be used for the study of the role of calcium in histamine release, (2) the action of calcium in the histamine release reaction seems to be related to the microtubular system, (3) cyclic AMP may potentiate histamine release when the action of calcium is inhibited.

Potentiation of dextran-induced histamine release from rat mast cells by phosphatidyl serine.

AbstractPhosphatidyl serine in 1–50 μg/ml concentrations markedly potentiates histamine release in‐duced by dextran in vitro from the mixed peritoneal cells of rats. The release occurs within one‐half minute, thus resembling the anaphylactic histamine release. The histamine release from isolated pure populations of mast cells, which generally respond poorly to dextran, was largely restored by phosphatidyl serine. The media, employed for the isolation of mast cells, viz. serum albumin, Ficol and acacia, were found to inhibit histamine release. The albumin inhibition could be overcome by phopshatidyl serine, which enhanced the release in spite of the presence of albumin. Serum albumin was found to bind phospholipids, an effect which may be related to the inhibition of histamine release caused by albumin. The effect of some inhibitors of the ATPase system was studied. Ouabain in 1–10 mM concentration neither affected the dextran‐induced histamine release nor its potentiation by phopshatidyl serine. Ethacrynic acid (1 mM) had some inhibitory effect on histamine release by dextran alone and dextran + phosphatidyl serine. Oligomycin (1 μg/ml) had very little effect on histamine release induced by dextran alone, but completely blocked the potentiation of histamine release caused by phosphatidyl serine.

Naturally occurring human antiglobulins with specificity for E.

Human sera have been examined for antibodies with specific reactivity for gammaE using the tanned cell hemagglutination test. Cells tanned with three different gammaE myeloma proteins provided a reproducible test system. Inhibition of agglutination reactions by gammaE proteins, but not by gammaG, gammaA, gammaM, or gammaD confirmed the specificity of these reactions. 8.5% of 304 serial serum samples obtained from miscellaneous hospitalized patients showed clear-cut anti-gamma-globulins with specificity for gammaE. In most of these instances no definite clinical history of concomitant allergic disorders could be obtained. 53% of 73 patients with well-established allergic disorders (hay fever, extrinsic asthma) showed serum anti-gamma-globulins with reactivity for gammaE. Some patients studied before and after desensitization to Bermuda grass allergen showed an increase in titer or a conversion from negative to positive reactions for anti-gammaE antibodies following several month courses of progressive desensitization. Gradient and gel filtration studies indicated that anti-gammaE globulins were 19S gammaM in all instances. No clear correlation was noted between quantitative serum gammaE levels and titer of anti-gammaE antibodies.19S serum fractions with anti-gammaE antibody activity did not release histamine from normal human peripheral blood leukocytes, whereas specific rabbit anti-gammaE antisera consistently induced leukocytic histamine release. Moreover, macroglobulin fractions with anti-gammaE activity did not block allergen-specific leukocyte histamine release induced by in vitro leukocyte challenge with allergens such as Bermuda grass and leukocytes from allergic donors. In some instances 19S human serum fractions with anti-gammaE activity appeared to potentiate histamine release when incubated concomitantly with specific allergen and leukocytes from allergic individuals.

The inhibition of mast cell damage and histamine release in anaphylaxis by pyridine and diphosphopyridine nucleotidase inhibitors. Comparison with compound 48/80.

In rats and guinea-pigs both mast cell damage and histamine release in anaphylaxis were inhibited by pyridine, nicotinamide, diethylnicotinamide, nicotinic acid, isonicotinic acid and isonicotinic acid hydrazide, which are known to be inhibitors of diphosphopyridine nucleotidases. On the other hand these compounds potentiated histamine release and mast cell damage by compound 48/80 in guinea-pigs although inhibiting the same phenomena in rats. The relationship of these findings with the mechanism of histamine liberation in anaphylaxis is discussed.