Britta Lundquist

Inhibitory Effect of Glucocorticosteroids on Anti‐IgE‐Induced Histamine Release from Human Basophilic Leukocytes: Evidence for a Dual Mechanism of Action

Anti‐IgE‐induced histamine release from human leukocytes is inhibited when the cells before challenge are cultured overnight in the presence of glucocorticoids (GCSs). The present report suggests that the GCSs might exert their effect by at least a dual mechanism of action. Histamine release was induced by a suboptimum concentration of anti‐IgE. When the release recorded in the presence of the steroid is plotted against the release recorded in its absence, the data points of several experiments fit a regression line characterized by two parameters: its slope and its intercept with the abscissa. Structure‐activity examination with selected GCSs indicates that the orders of potency for affecting these two parameters are not identical, Furthermore, pulse experiments suggest that the cells require different times of contact with the steroid to express inhibition according to the two parameters. The removal of adherent cells or platelets did not markedly affect the degree of leukocyte histamine release or its inhibition by a given GCS, suggesting that the steroid interacts directly with the basophil. Finally. steroid‐induced inhibition was not affected by the putative phospholipase A2‐inhibitor p‐bromophenacylbromide (BPB) or the 5‐lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA).

Induction of human basophil histamine release by a novel protein kinase C activator, sn-1,2-isopropylidene-3-decanoyl-glycerol (IpOCOC9): partial characterization of secretagogue characteristics.

Human leukocytes were found to release histamine at exposure for the synthetic glyceride derivative sn‐1,2‐isopropylidene‐3‐decanoyl‐glycerol (IpOCOC9). The following characteristics for the IpOCOC9‐induced basophil histamine release were recorded. A. In the order of 25% of the cellular histamine content was extruded at 206 μmol/l and 45% at 690 μmol/l of the compound, respectively. B. Removal of extracellular Ca2+ variably affected IpOCOC9‐triggered release. C. The presence of N‐ethylmaleimide (10 μmol/l) or p‐bromophenacylbromide (10 μmol/l) markedly reduced IpOCOC9‐induced histamine release. D. The time course of the release triggered by IpOCOC9 was intermediate to those characterizing the release triggered by 4β‐phorbol 12‐myristate 13‐acetate (PMA) and by formyl‐methionyl‐leucyl‐phenylalanine (FMLP). E. Cells desensitized to IgE‐receptor‐mediated stimulation were hyperresponsive to stimulation with IpOCOC9. F. Cells treated with a low concentration of 2‐deoxyglucose were not hyperresponsive to IpOCOC9. These data show that IpOCOC9, a PMN/leukocyte protein kinase C stimulator, acts as a non‐cytotoxic secretagogue for human basophils with a mode of action which in some, but not all respects, mimics that of PMA. In particular, IpOCOC9‐triggered release resembles that reported by other authors for hyperosmolar triggering of release by mannitol.

Anti-IgE and Con A-induced histamine release from mast cells of four rat strains: correlation with total serum IgE.

Anti-IgE- and Con A-induced histamine release from serosal mast cells were compared to each other and to total serum levels of IgE in non-immunized, alum-injected, and Silica gel-injected rats of the BN, Fischer, PVG, and SD strains. The results indicate that the degree of anti-IgE-and Con A-induced release is strain-dependent and varies with immunization conditions. Furthermore, there is a gross but not complete correlation between the degree of serosal mast cell histamine release induced by the two secretagogues. However, Con A- or anti-IgE-induced release could significantly be correlated to serum levels of total IgE only in the Fischer strain but not in the BN or the PVG strains. In the SD strain, Con A-induced release correlated to serum IgE levels in Silica gel-injected but not in alum-injected animals.

Anti-IgE-Induced Histamine Release from Human Basophilic Leukocytes: Inhibition Depends on Nature and Concentration of Inhibitor and Secretagogue

Histamine release from human basophilic leukocytes was induced by increasing concentrations of anti‐lgE in the presence of various concentrations of 2‐deoxyglucose (2‐DOG), the histamine H2‐receptor agonist dimaprit, theophylline, or enprofylline (a new antiasthmatic xanthine derivative). The results show that the degree of inhibition produced by each agent differed with the concentration of anti‐IgE used and with the nature and concentration of the inhibitor. These data indicate that great care should be used when characterizing an inhibitor of mediator release by simply giving a figure for the per cent inhibition of release observed in its presence.

The Glucocorticosteroid, Budesonide, Partially Blocks Histamine Release from Human Lung Tissue in Vitro

IgE‐receptor dependent, but not A23187‐induced, histamine release from passively sensitized chopped human lung tissue, or from a dispersed lung cell population obtained from the tissue after enzymatic digestion, is reduced after incubation overnight of cells/tissue with the glucocorticosteroid budesonide (10‐7M). Since the inhibitory effect of budesonide is reduced in the continuous presence of diluted reagin‐rich serum used for passive sensitization, but not in the presence of heat‐inactivated serum, it is suggested that the glucocorticosteroid acts by reducing the binding of IgE‐antibody to the target cell(s).

Immunologically induced pleural and peritoneal mast cell histamine release: Difference in responsiveness in relation to secretagogue and rat strain used

Responsiveness was compared for cell populations harvested from the peritoneal and pleural cavities of rats with respect to histamine release induced by specific antigen, anti-IgE, and Con A. Cell populations were obtained from Fischer, PVG or Sprague-Dawley (SD) rats, which were either untreated or immunized with 10 μg ovalbumin together with 100 mg alum intraperitoneally. Mast cell histamine release was examined with crude cell populations. The results show that differences in response capacity to the various secretagogues employed do exist between pleural and peritoneal cells in Fischer and PVG strains but under the present circumstances apparently not in SD rats. These differences vary in magnitude with the secretagogue employed and (for cells from immunized animals) with the time elapsed between immunization and test. In PVG rats, neither pleural nor peritoneal mast cell histamine release induced by antigen paralleled serum OA-IgE antibody levels. Furthermore, an increase in anti-IgE induced release of histamine from serosal mast cells occurred in parallel with a decrease in total serum IgE levels. These data indicate that the functional differences observed with respect to release properties of the two cell populations are due not only to intrinsic differences in mast cell populations but also to differences in reaginic antibodies sensitizing the cells.

Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis‐trans isomerase in a secretagogue specific manner

Bergstrand H, Lundquist B. Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis‐trans isomerase in a secretagogue specific manner.

Modulation of human leukocyte histamine release by sn‐1,2‐isopropylidene‐3‐decanoyl‐glycerol and decanoic acid cyclopentyl methylester in comparison with effects of synthetic diacylglycerols and a phorbol ester

Previous studies have shown that the glyceride derivative, sn‐1,2 ‐isopropylidene‐3‐decanoyl‐glycerol (IpOCOC9), can trigger human leukocyte histamine release. Approximately 25 % of the total cellular histamine content is extruded in the presence of 206 # of IpOCOC9; at 69 μM, however, the secretagogue action of the compound is marginal. The characteristics of the release induced by IpOCOC9 are closely similar to those reportedly recorded at hyperosmolar triggering of basophils with mannitol, and in many respects they also mimic those observed at phorbol ester‐induced histamine release. The compound decanoic acid cyclopentyl methylester (DACPME), a structural analogue of IpOCOC9, fails to induce histamine release. IpOCOC9, but not DACPME, stimulates human polymorphonuclear leukocyte cytosolic Ca2+− and phospholipid‐dependent his‐tone III‐S kinase activity (unpublished observations). The secretagogue action of IpOCOC9, has therefore tentatively, at least partly, been attributed to a direct protein kinase C activation. In the present studies, we examined the influence of IpOCOC9 and DACPME on histamine release triggered by an ensuing exposure to anti‐IgE, the calcium ionophore A23187, formyl‐methionyl‐leucyl‐phenylalanine (EMLP), or 4β‐phor‐bol 12‐myristate 13‐acetate (PMA). It is shown that IpOCOC9‐treatment of cells results in either enhancement or reduction of the release induced by anti‐IgE or by A23187, whereas FMLP‐induced release is consistently reduced and PMA‐induced release consistently enhanced by such a treatment. Treatment of cells with DACPME enhances but does not reduce anti‐IgE‐triggered release, whereas EMLP‐induced release is not affected. Pretreatment of the cells with other putative protein kinase C activators like PMA, sn‐1‐oleoyl‐2‐acetyl‐glycerol (OAC), 1,2‐dioctanoyl‐glycerol (DiCg) or the glycerol derivative sn‐1,2‐diacetyl‐3‐decanoyl‐glycerol (DiC2OCOC9) affects secretagogue‐induced basophil histamine release according to specific patterns similar to but not identical with those recorded for IpOCOC9 and DACPME. Thus, e.g., DiC2OCOC9 consistently reduces but does not enhance anti‐IgE‐triggered release. These data show that limited structural changes of IpOCOC9 may qualitatively affect its modulating properties in the human basophil histamine release system.

Anti-ige-induced Histamine-release From Rat-tissues Passively Sensitized Invivo With Myeloma Ige Differs With Strain and Mast-cell Source

Four different strains of rats, BDII, E3, LE, and OM/N, each with a low basal serum level of IgE, were examined with respect to anti-IgE- and ConA-induced release of histamine from serosal mast cells and chopped lung tissue. Tests were performed before and three days after i.p. injection of a graded dose of myeloma IgE (IR 162)-containing ascitic fluid. There was a clearcut strain difference in response capacity with respect to ConA- and anti-IgE-induced release of histamine from serosal mast cells before myeloma IgE-injection. Response capacity increased in some but not all strains after myeloma IgE injection; increase in response capacity of serosal mast cells did not correlate to that of chopped lung tissue. Analogous findings were observed when two of the strains, LE and E3, were passively sensitized by i.p. injection with serum containing another myeloma IgE (IR2). These results indicate that differences exist between mast cells of different rat strains, and within strain between mast cells of various tissues in capacity to become sensitized to myeloma IgE.

Anti-IgE- and ConA-induced histamine release from human basophilic leukocytes: the existence of differences in relative responses within individuals

Histamine release was induced from human blood leukocytes with Concanavalin A (ConA) and two different preparations of anti-IgE. A dose-response curve was constructed for each cell population and secretagogue. No qualitative difference in response pattern was observed with the two anti-IgEs; however, the relative release-inducing efficacy of ConA and anti-IgE seemed to vary with the individual providing the cells. These findings indicate that release induced by ConA is not completely equivalent to that induced by anti-IgE.