Mechanism of histamine release from isolated mast cell granules by calcium with phosphatidyl serine

Histamine is released from isolated mast cell granules with intact membranes by calcium (10 mM) in presence of phosphatidyl serine (25-50 micrograms/ml). The release occurs both in Krebs-Ringer solution and in sucrose solution without monovalent cations, but the release in Krebs-Ringer solution is somewhat higher. The histamine release is associated with increased calcium uptake. But calcium is taken up much faster, within 5 sec, while it takes several minutes before histamine release is completed. The observations suggest a rapid uptake of calcium to the granule membrane, from which it may be more slowly released to the matrix, displacing histamine from its binding sites. Phosphatidyl serine with calcium could also conceivably change the membrane permeability causing increased influx of sodium ions, thus accounting for the mild enhancement of the release in Krebs-Ringer solution.     

Inhibition by cromoglycate of histamine release from rat peritoneal mast cells induced by mixtures of dextran, phosphatidyl serine and calcium ions

1 Dextran releases histamine from rat peritoneal mast cells in the presence but not in the absence of phosphatidyl serine (PS). With PS (10 mug/ml) present the effect of dextran was concentration-dependent in the range of 0.2-6 mg/ml.2 PS releases little histamine on its own but mixed with dextran (6 mg/ml) produces a graded effect in the range of 0.3-10 mug/ml.3 The combination of dextran and PS releases no histamine in a medium containing less than 0.1 mM calcium. As the calcium concentration is increased, release occurs and a maximum is reached at calcium 1 mM; at higher concentrations release falls off sharply.4 Histamine release by the combination of dextran (6 mg/ml), PS (10 mug/ml) and calcium (1.8 mM) is inhibited by cromoglycate in the same range (1-30 muM) that inhibits anaphylactic histamine release from rat peritoneal cells.5 Inhibition by cromoglycate occurred with all dextran concentrations tested (0.2-15 mg/ml) but high concentrations of PS (30 and 100 mug/ml) overcame the effect of cromoglycate (2 and 10 muM). Calcium concentrations above 1 mM augmented inhibition by cromoglycate 2 and 10 muM.     

Mechanism of histamine release by alpha-chymotrypsin from isolated rat mast cells.

Alpha-chymotrypsin (CT) was modified chemically and physically by the treatments with diisopropyl fluorophosphate, L-(1-tosylamide-2-phenyl) ethylchloromethylketone, hydrogen peroxide and heat. After these treatments, CT lost or decreased both the enzymic activity and ability of releasing histamine from rat mast cells. Ca++ was essential for histamine release by CT, while it enhanced only slightly the enzymic activity. Process of histamine release by CT could be separated into two stages: CT-dependent but not Ca++-dependent, and Ca++-dependent but not CT-dependent. The activated state of mast cells produced by CT decayed rapidly at 37 degrees C in the absence of Ca++, but these cells responded to Ca++ by adding CT once again, suggesting reconstitution of cell membrane structure affected by CT. Isoproterenol, epinephrine, prostaglandin E1, and dibutyryl-cyclic AMP (0.01-0.1 mM) did not inhibit release of histamine induced by CT. Neither theophylline (0.01-0.1 mM) alone nor the combinations of these cyclic AMP-active agents with theophylline inhibited the release of histamine. But, in the presence of papaverine (0.01-0.1 mM) a marked, dose-dependent inhibition was observed. These data suggest that 1) release of histamine by CT from rat mast cells is causally related to its hydrolytic activity, 2) this activity causes a reversible change on mast cell membrane which probably facilitates Ca++-influx through the cell membrane, and 3) there are subtle differences among CT, compound 48/80 and antigens concerning the effect of cyclic AMP-active agents in histamine-releasing mechanisms in mast cells.     

The influence of tetradecanoyl-phorbol-acetate (TPA) on histamine release from isolated rat mast cells

A detailed investigation of the influence of tetradecanoyl-phorbol-acetate (TPA) on isolated rat mast cells was undertaken in order to explore the possible involvement of protein kinase C in histamine release. TPA alone could induce histamine release in a medium without calcium, whereas 1 mM CaCl2 suppressed the release. TPA in combination with a low concentration of the ionophore A23187 induced a considerable histamine release. Preincubation with TPA followed by incubation with the ionophore induced a similar release at low concentrations of TPA (less than or equal to 2.5 nM) whereas the response was reduced at higher concentrations of TPA. The inhibition after preincubation with TPA was almost at a maximum within 2 min and was due to a decreased rate of release. TPA could also increase antigen-induced histamine release. After preincubation the potency of low concentrations of TPA increased, whereas higher concentrations (50 nM) became inhibitory. The effects of preincubation were almost fully expressed after 2 min and were not due to altered kinetics of the release. The interaction of oleoylacetylglycerol (OAG) with the ionophore A23187 and with antigen resembled that of TPA, but OAG was considerably less potent. Preincubation with TPA was inhibitory to the histamine release induced by compound 48/80, particularly in the absence of calcium. The release induced by TPA and the ionophore or antigen was calcium-dependent and energy-requiring, and the effects of TPA persisted after washing the cells before exposure to antigen or the ionophore. Preincubation with the protein kinase C inhibitor isoquinolinesulfonyl-methylpiperazine (H7) slightly enhanced the histamine release induced by the combination of TPA and the ionophore.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells

Vancomycin and certain fungicides may cause anaphylactoid reactions. We investigated the effects of vancomycin, miconazole and fluconazole on histamine release in rat peritoneal mast cells. Vancomycin and miconazole provoked histamine release in a dose-dependent manner. In contrast, fluconazole did not provoke histamine release at concentrations of 3 x 10(-6)-3 x 10(-3) M. Vancomycin is efficacious in the treatment of gram-positive bacterial infections; patients presenting themselves with mixed infections require concomitant therapy with a second antimicrobial agent. We investigated the effect of fosfomycin sodium, cilastatin sodium or fluconazole on vancomycin-induced histamine release. Fosfomycin sodium inhibited vancomycin-induced histamine release but neither cilastatin sodium nor fluconazole inhibited it in the mole ratios of daily doses used in humans. These results suggest that vancomycin and miconazole provoke histamine release in rat mast cells, but that fluconazole probably does not, while fosfomycin sodium may inhibit vancomycin-induced histamine release.     

Effect of ryanodine on histamine release from rat peritoneal mast cells induced by anti-IgE.

Ryanodine strongly inhibited histamine release from rat peritoneal mast cells induced by anti-IgE. Ryanodine also inhibited Ca(2+)-mobilization from the intracellular Ca(2+)-store as well as histamine release in mast cells activated by anti-IgE. These results suggest that the effect of ryanodine on histamine release from rat mast cells might be due to the inhibition of Ca2+ release from the intracellular Ca2+ store.     

Inhibitory effect of phloretin on histamine release from isolated rat mast cells

The ability of the flavonoid phloretin to inhibit histamine release from rat mast cells varied considerably with the releasing agent investigated. The response to the combination of the ionophore A23187 and the phorbol ester TPA and to suboptimal concentrations of the ionophore (0.5 microM) was potently inhibited (IC50 about 5 microM), whereas phloretin was less potent against responses to the ionophore (1 microM) (IC50 of 17 microM), to antigen alone and in combination with TPA (IC50 of 30-50 microM), to TPA in the absence of calcium (IC50 of 50 microM) and to compound 48/80 in the absence and presence of calcium (IC50 of 60-90 microM). The inhibition by phloretin at concentrations above 10 microM was partly counteracted by glucose (5 mM) indicating effects on oxidative metabolism. The flavonoid quercetin was equally potent in inhibiting histamine release induced by antigen, the ionophore at different concentrations and in combination with TPA (IC50 of 20 microM). Although not conclusive, the results are consistent with an inhibition of protein kinase C by phloretin at concentrations below 10 microM. At higher concentrations unspecific actions become apparent and phloretin therefore seems to be of limited utility as a probe for signal-pathways in cell responses.     

Sphingosine inhibition and promotion of histamine release from isolated rat mast cells.

Sphingosine inhibited the histamine release induced by antigen, compound 48/80 with and without calcium, and the combination of TPA and the ionophore A23187. The inhibition occurred in the concentration range 1-3 microM, where no sign of cytotoxicity was noted. Preincubation for 5-10 min was needed for inhibition, and the effect persisted after washing of the cells. No inhibition was found with optimal concentrations of the ionophore or with TPA present during the preincubation. Sphingosine in combination with suboptimal concentrations of the ionophore could induce a considerable histamine release. This response was dependent on energy and was potently inhibited by the flavonoid phloretin. After preincubation with TPA, sphingosine exerted a pronounced potentiation of the response to very low concentrations of the ionophore. The findings regarding inhibitory effects of sphingosine do not seem to be compatible with a selective action on protein kinase C. The ability to synergize with the ionophore and to potentiate the effect of preincubation with TPA resembles previous findings with palmitoylcarnitine and suggests that sphingosine can stimulate mast cells by activation of protein kinase C.     

Characteristics of histamine and serotonin release from rat mast cells induced by thymic peptides.

Thymopoietin peptides release histamine and serotonin from rat mast cells. The release has the characteristics of other basic secretagogues in that it occurs rapidly, does not require extracellular Ca2+ ions, and is inhibited by benzalkonium chloride (BAC). These similarities indicate that chemically different basic compounds have common mechanisms for histamine and serotonin release from rat mast cells.     

Anthracycline-induced histamine release from rat mast cells

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.     

The mechanism of histamine release induced by the ionophore X537A from isolated rat mast cells. II. The relationship between increase of cell volume and histamine release.

The ionophore X537A induced swelling of isolated rat mast cells parallel to histamine release. Both actions were depressed by extracellular calcium and BSA, temperatures below 37 degrees C, NEM, PMSF, and TTX, and were enhanced by high potassium and pretreatment of the cells with ATP. DSCG, theophylline, and DFP enhanced the histamine release noted after 10 min of incubation without influencing the swelling action of X537A. The swelling action could not be separated from histamine release and it is suggested that it might be inherent in the mechanism of secretion induced by X537A. The present results further distinguish histamine release induced by the two ionophores X537A and A23187.     

Induction of histamine release from rat peritoneal mast cells by histatins.

Human salivary histatins (Hsts), which belong to a salivary polypeptide family, have potent antifungal activity against Candida albicans and Cryptococcus neoformans, and are expected to be useful as therapeutic reagents against Candida species. However, little is known about the effect of Hsts on host immune systems. Thus we conducted a series of in vitro experiments with rat mast cells to determine whether histatin 5 (Hst 5) or histatin 8 (Hst 8) has a histamine-releasing effect on mast cells. Both Hst 5 and Hst 8 induced histamine release from rat peritoneal mast cells in a dose-dependent manner (10(-9) to 10(-5) M). Hst 5 had a stronger releasing effect than Hst 8. The histamine release induced by Hst 5 (10(-6) M) was increased by the presence of 0.5 mM Ca2+, but decreased by 2mM Ca2+. Alternatively, the histamine release induced by Hst 8 (10(-6) M) was inhibited by the presence of Ca2+ (0.5 to 2 mM). These results suggest that Hsts have limited usefulness as therapeutic agents due to induction of histamine release from mast cells.