Livedo reticularis and congenital hypogammaglobulinemia.
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Adult↗
Biomedical subjects
G Marone
Publications and source records attributed to G Marone.
Characterization of the anti-inflammatory effect of FK-506 on human mast cells.
We have examined the effects of FK-506 and of the struturally related macrolide rapamycin, which bind with high affinity to a specific binding protein (FKBP), to evaluate the involvement of this protein in the release of preformed (histamine) and de novo synthesized inflammatory mediators (sulfidopeptide leukotriene C4 and prostaglandin D2) from mast cells isolated from human lung parenchyma. FK-506 (0.1 to 300 nM) concentration dependently inhibited histamine release from lung parenchymal mast cells activated by anti-IgE. FK-506 was more potent in lung mast cells than in basophils (IC50 = 1.13 +/- 0.46 nM vs 5.28 +/- 0.88 nM; p less than 0.001), whereas the maximal inhibitory effect was higher in basophils than in lung mast cells (88.4 +/- 2.5% vs 76.4 +/- 3.8%; p less than 0.01). FK-506 had little or no inhibitory effect on histamine release from lung mast cells challenged with compound A23187, whereas it completely suppressed A23187-induced histamine release from basophils. FK-506 also inhibited the de novo synthesis of 5-lipoxygenase (sulfidopeptide leukotriene C4) and cyclo-oxygenase (prostaglandin D2) metabolites of arachidonic acid from mast cells challenged with anti-IgE. Unlike in basophils, Il-3 (3 to 30 ng/ml) did not modify anti-IgE- or A23187-induced histamine release from lung mast cells nor did it reverse the inhibitory effect of FK-506. Rapamycin (3 to 300 nM) had little or no effect on the release of histamine from lung mast cells, but it was a competitive antagonist of the inhibitory effect of FK-506 on anti-IgE-induced histamine release from human mast cells with a dissociation constant of about 12 nM. These data indicate that FK-506 is a potent anti-inflammatory agent that acts on human lung mast cells presumably by binding to a receptor site (i.e., FKBP).
Anti-Inflammatory Agents, Non-Steroidal↗
FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells.
FK-506, a macrolide that binds with high affinity to a specific binding protein, and the structurally related macrolide rapamycin (RAP) were compared to cyclosporin A (CsA) for their effects on the release of preformed (histamine) and de novo synthesized (peptide leukotriene C4) inflammatory mediators from human basophils. FK-506 (1 to 300 nM) concentration dependently inhibited histamine release from basophils activated by Der p I Ag, anti-IgE, or compound A23187. FK-506 was more potent than CsA when basophils were challenged with Ag (IC50 = 25.5 +/- 9.5 vs 834.3 +/- 79.8 nM; p less than 0.001), anti-IgE (IC50 = 9.4 +/- 1.7 vs 441.3 +/- 106.7 nM; p less than 0.001), and A23187 (IC50 = 4.1 +/- 0.9 vs 36.7 +/- 3.8 nM; p less than 0.001). The maximal inhibitory effect of FK-506 was higher than that caused by CsA when basophils were activated by Der p I (80.0 +/- 3.6 vs 49.5 +/- 4.7%; p less than 0.001) and anti-IgE (90.4 +/- 1.8 vs 62.3 +/- 2.9%; p less than 0.001). FK-506 had little or no effect on the release of histamine caused by f-met peptide, phorbol myristate (12-tetradecanoyloxy-13-acetoxy-phorbol), and bryostatin 1. RAP (30 to 1000 nM) selectively inhibited only IgE-mediated histamine release from basophils, although it had no effect on mediator release caused by f-met peptide, A23187, 12-tetradecanoyloxy-13-acetoxy-phorbol, and bryostatin 1. FK-506 also inhibited the de novo synthesis of sulfidopeptide leukotriene C4 from basophils challenged with anti-IgE. Low concentrations of FK-506 and CsA synergistically inhibited the release of mediators from basophils induced by anti-IgE or compound A23187. IL-3 (3 and 10 ng/ml), but not IL-1 beta (10 and 100 ng/ml), reversed the inhibitory effect of both FK-506 and CsA on basophils challenged with anti-IgE or A23187. RAP was a competitive antagonist of the inhibitory effect of FK-506 on A23187-induced histamine release from basophils with a dissociation constant of about 30 nM. In contrast, RAP did not modify the inhibitory effect of CsA on A23187-induced histamine release. These data indicate that FK-506 is a potent antiinflammatory agent that acts on human basophils presumably by binding to a receptor site (i.e., FK-506 binding protein).
Anti-Bacterial Agents↗
Human basophil releasability. VIII. Increased basophil releasability in patients with scleroderma.
We evaluated basophil releasability in 16 female patients with scleroderma (systemic sclerosis) and in 16 normal age- and sex-matched donors. Basophils from patients with scleroderma released significantly more histamine "spontaneously" than did those from normal donors (12.9 +/- 2.1% versus 4.5 +/- 0.7%; P less than 0.0005). Basophil reactivity (maximal percentage histamine release) to anti-IgE was higher in patients with scleroderma than in controls (57.0 +/- 7.5% versus 35.4 +/- 7.8%; P less than 0.05). Basophil sensitivity (the concentration of anti-IgE that causes 40% of maximal percentage histamine release) to anti-IgE in scleroderma patients was similar to that found in controls (4.6 +/- 2.8 x 10(-2) micrograms/ml versus 2.3 +/- 1.0 x 10(-1) micrograms/ml; P not significant). Scleroderma patients also showed enhanced releasability compared with that of the controls when challenged in vitro with interleukin-3 (8.3 +/- 1.7% versus 3.2 +/- 0.6%; P less than 0.01). Releasability induced by the formyl-containing tripeptide, f-met peptide, was significantly higher in the scleroderma patients than in the controls at the 2 lower concentrations used. No differences in basophil reactivity and sensitivity to f-met peptide and calcium ionophore A23187 were found between patients and normal donors. These results show that spontaneous basophil releasability and releasability in response to IgE cross-linking and activation of interleukin-3 receptors are increased in patients with scleroderma.
Adult↗
General anaesthetics induce only histamine release selectively from human mast cells.
We have examined the in vitro effects of increasing concentrations of propofol (5-70 micrograms ml-1), ketamine (10(-6)-10(-3) mol litre-1) and thiopentone (10(-5)-8 x 10(-4) mol litre-1) on the release of preformed histamine and de novo synthesized mediators (peptide leukotriene C4 (LTC4) or prostaglandin D2 (PGD2] from human basophils and mast cells isolated from lung parenchyma and skin tissue and from heart fragments. Propofol, ketamine and thiopentone failed to induce the release of histamine and de novo synthesis of LTC4 from basophils. Propofol induced histamine release from lung (mean 8.6 (SEM 1.6)%) and skin mast cells (3.8 (1.5)%), but not from heart mast cells. Ketamine caused release of histamine from lung (6.2 (0.9)%) and skin mast cells (2.5 (1.5)%). Thiopentone caused a small amount of histamine release from lung mast cells (3.1 (1.2)%). Propofol, ketamine and thiopentone did not induce de novo synthesis of PGD2 and LTC4 from lung and skin mast cells. These results demonstrate that general anaesthetics induce only histamine release selectively from human mast cells.
Anesthetics↗
Heterogeneity of human mast cells and basophils in response to muscle relaxants.
The authors studied the effects of increasing concentrations 10(-5)-10(-3) M) of four muscle relaxants (succinylcholine, d-tubocurarine, vecuronium, and atracurium) on histamine release from peripheral blood basophils and mast cells isolated from human lung parenchyma, skin tissues, and heart fragments. Basophil granulocytes released less than 5% of their histamine content when incubated with any one of the muscle relaxants tested. In contrast, mast cells showed a significant heterogeneity in response to different muscle relaxants. Succinylcholine did not induce histamine release from any type of mast cell, and only high concentrations of d-tubocurarine (10(-3) M) caused histamine release from skin and lung mast cells. Vecuronium concentration-dependently induced histamine release from skin and lung--but not from heart mast cells--to a maximum of 7.2 +/- 2.1% and 4.9 +/- 1.4%, respectively. Atracurium concentration-dependently caused significant histamine release from skin and lung mast cells to a maximum of 46.2 +/- 15.1% and 30.6 +/- 6.0%, respectively. Atracurium (5 x 10(-5) - 2 x 10(-4) M) also induced histamine release from heart mast cells. The histamine release process from both lung and skin mast cells caused by atracurium and vecuronium was extremely rapid (t1/2 = less than 1 min). The releasing activity of atracurium and vecuronium on lung and skin mast cells was not reduced, and not abolished, by lowering the temperature of the incubation buffer to 22 degrees C and 4 degrees C. Extracellular calcium did not affect the capacity of atracurium and vecuronium to induce histamine release from lung and skin mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Basophils↗
Ciclosporin A inhibits mediator release from human Fc epsilon RI+ cells by interacting with cyclophilin.
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Amino Acid Isomerases↗
Antiinflammatory effect of FK 506 on human basophils.
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Adjuvants, Immunologic↗
Adenosine receptors of human leukocytes--II. Characterization of an inhibitory P-site.
We have investigated the effects of 2',5'-dideoxyadenosine (DDA), 9'-beta-D-arabinofuranosyladenine (ARA), and 9-beta-D-xylofuranosyladenine (XFA), which have been classified as P-site adenosine agonists, on the cyclic adenosine 3',5'-monophosphate (cAMP) metabolism of human lymphocytes and polymorphonuclear leukocytes (PMNs). DDA (10(-5)-2 x 10(-4) M), ARA and XFA caused a dose-dependent decrease in cAMP content of human lymphocytes. In addition to decreasing lymphocyte cAMP levels, DDA, ARA, and XFA markedly inhibited the effects of many adenylate cyclase-stimulating agents including beta-adrenergic stimuli, prostaglandin E1 (PGE1), histamine, adenosine, forskolin and cholera toxin. Theophylline and 3-isobutyl-1-methylxanthine, which are known antagonists of adenosine A1/Ri and A2/Ra receptors, did not modify the inhibiting effects of DDA. Mn2+ (1 mM) increased the sensitivity to inhibition of adenylate cyclase agonists by DDA. We also search for the presence of adenosine P-sites in human PMNs. DDA caused a significant decrease of PMN cAMP levels only at the highest concentrations used (2 x 10(-4) M). In contrast, even low concentrations of DDA (10(-6)-10(-4) M) concentration-dependently blocked the stimulatory effect of PGE1 and forskolin on PMN cAMP accumulation. The results support the existence of a purine P-site that regulates cAMP metabolism of human lymphocytes and PMNs.
Adenosine↗
Protein L. A bacterial Ig-binding protein that activates human basophils and mast cells.
Peptostreptococcus magnus strain 312 (10(6) to 10(8)/ml), which synthesizes a protein capable of binding to kappa L chains of human Ig (protein L), stimulated the release of histamine from human basophils in vitro. P. magnus strain 644, which does not synthesize protein L, did not induce histamine secretion. Soluble protein L (3 x 10(-2) to 3 micrograms/ml) induced histamine release from human basophils. The characteristics of the release reaction were similar to those of rabbit IgG anti-Fc fragment of human IgE (anti-IgE): it was Ca2(+)- and temperature-dependent, optimal release occurring at 37 degrees C in the presence of 1.0 mM extracellular Ca2+. There was an excellent correlation (r = 0.82; p less than 0.001) between the maximal percent histamine release induced by protein L and that induced by anti-IgE, as well as between protein L and protein A from Staphylococcus aureus (r = 0.52; p less than 0.01). Preincubation of basophils with either protein L or anti-IgE resulted in complete cross-desensitization to a subsequent challenge with the heterologous stimulus. IgE purified from myeloma patients PS and PP (lambda-chains) blocked anti-IgE-induced histamine release but failed to block the histamine releasing activity of protein L. In contrast, IgE purified from myeloma patient ADZ (kappa-chains) blocked both anti-IgE- and protein L-induced releases, whereas human polyclonal IgG selectively blocked protein L-induced secretion. Protein L acted as a complete secretagogue, i.e., it activated basophils to release sulfidopeptide leukotriene C4 as well as histamine. Protein L (10(-1) to 3 micrograms/ml) also induced the release of preformed (histamine) and de novo synthesized mediators (leukotriene C4 and/or PGD2) from mast cells isolated from lung parenchyma and skin tissues. Intradermal injections of protein L (0.01 to 10 micrograms/ml) in nonallergic subjects caused a dose-dependent wheal-and-flare reaction. Protein L activates human basophils and mast cells in vitro and in vivo presumably by interacting with kappa L chains of the IgE isotype.
Antigens, Differentiation, B-Lymphocyte↗
Cyclosporin A rapidly inhibits mediator release from human basophils presumably by interacting with cyclophilin.
We have examined the effects of cyclosporin A (CsA) and a series of CsA analogs that bind with decreasing affinity to cyclophilin, to evaluate the involvement of this protein in the release of preformed (histamine) and de novo synthesized (peptide leukotriene C4; LTC4) mediators of inflammatory reactions from human basophils. CsA (8 to 800 nM) concentration-dependently inhibited (5 to 60%) histamine release from peripheral blood basophils challenged with anti-IgE. CsA was more potent (92.6 +/- 1.8 vs 59.1 +/- 4.5%; p less than 0.001) and, at low concentrations, more effective when the channel-operated influx of Ca2+ was bypassed by the ionophore A23187 (IC40 = 24.1 +/- 3.9 vs 105.5 +/- 22.2 nM; p less than 0.05). CsA had no effect on the release of histamine caused by phorbol myristate and bryostatin 1 that activate different isoforms of protein kinase C. Inhibition of histamine release from basophils challenged with anti-IgE was not abolished by washing (three times) the cells before anti-IgE challenge. CsA also inhibited the de novo synthesis of LTC4 from basophils challenged with anti-IgE. The inhibitory effect of CsA was very rapid, and the drug, added from 1 to 10 min during the reaction, inhibited the ongoing release of histamine caused by anti-IgE and by A23187. The experiments with CsA analogs (CsG, CsC, CsD, and CsH) showed that CsH, which has an extremely low affinity for cyclophilin, has no effect on basophil mediator release. In addition, there is a significant correlation between the concentrations of CsA, G, C, and D that inhibited by 30% the histamine release induced by anti-IgE (r = 0.99; p less than 0.001) and by A23187 (r = 0.87; p less than 0.001) and their affinity for cyclophilin.
Antibodies, Anti-Idiotypic↗
Modulation of mediator release from human basophils and pulmonary mast cells and macrophages by auranofin.
Auranofin, a new orally absorbable gold compound, inhibits IgE-(anti-IgE) and non-IgE-mediated (f-met-peptide and the Ca2+ ionophore A23187) histamine release from human basophils. Auranofin inhibits the release of histamine induced by phorbol myristate (TPA) and bryostatin 1 both in the presence and absence of extracellular Ca2+. Increasing the Ca2+ concentrations in the extracellular medium does not reduce the inhibitory effect of auranofin on anti-IgE- or A23187-induced secretion. Auranofin inhibits the de novo synthesis of sulfidopeptide leukotriene C4 (LTC4) induced by anti-IgE from basophils and mast cells purified from human lung. However, in both systems auranofin has a significantly greater inhibitory effect on LTC4 release than on histamine secretion. Finally, auranofin induces a concentration-dependent inhibition of A23187-induced leukotrine B4 (LTB4) release from purified human lung macrophages. These data suggest that auranofin modulates the release of preformed (histamine) and de novo synthesized (LTC4 and LTB4) chemical mediators from human inflammatory cells isolated from peripheral blood and human lung tissues.
Auranofin↗
Human basophil releasability. VI. Changes in basophil releasability in patients with allergic rhinitis or bronchial asthma.
We evaluated basophil releasability in two groups of allergic patients with positive skin tests to Dermatophagoides pteronyssinus major allergen (Der p l) (29 adults with bronchial asthma and 17 with allergic rhinitis) and in 31 age-matched normal donors. Both basophil reactivity (maximal percent histamine release) and basophil sensitivity (the concentration that causes 50% of maximal percent histamine release: HC50) to Der p l in patients with asthma were similar to those in patients with allergic rhinitis. On the contrary, basophil reactivity to anti-IgE was significantly higher in patients with asthma (58.0 +/- 3.6%) than in patients with allergic rhinitis (46.3 +/- 5.2%; p less than 0.05). Both groups of patients showed an increased releasability compared to control subjects (27.3 +/- 4.6%; p less than 0.001), whereas there were no significant differences in basophil sensitivity to anti-IgE among the three groups of donors. Differences were also found with respect to basophil reactivity and sensitivity to f-met peptide, whereas no differences appeared when basophils from the three groups of donors were challenged with the Ca2+ ionophore A23187. There was a significant correlation between basophil reactivity and sensitivity to Der p l and to anti-IgE in both asthmatic and allergic rhinitis patients. A significant correlation was found between basophil reactivity and sensitivity to anti-IgE and serum IgE level only in patients with bronchial asthma, whereas no correlations were found in patients with allergic rhinitis. There was no correlation between in vivo mast cell releasability and in vitro basophil releasability in response to Der p l in either group of allergic patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Human basophil/mast cell releasability. VII. Heterogeneity of the effect of adenosine on mediator secretion.
5'-N-ethylcarboxamideadenosine (NECA) greater than 2-chloroadenosine greater than adenosine greater than N6-(R-phenyl-isopropyl)-adenosine (R-PIA) inhibited in vitro anti-IgE-induced histamine and peptide leukotriene C4 (LTC4) release from human basophils in a concentration-dependent fashion. Micromolar concentrations of adenosine, NECA and R-PIA potentiated the anti-IgE-stimulated release of histamine and LTC4 from human lung parenchymal mast cells. Submillimolar concentrations of adenosine, NECA and R-PIA inhibited in a concentration dependent manner the release of histamine and prostaglandin D2 (PGD2) from skin mast cells challenged with anti-IgE. These results demonstrate marked heterogeneity of the modulatory effect exerted by adenosine on mediator release from human basophils and mast cells.
2-Chloroadenosine↗
Pathophysiology of human basophils and mast cells in allergic disorders.
Basophil leukocytes and tissue mast cells are inflammatory cells that are found in virtually all human tissues. They appear to be involved in the pathogenesis of such allergic diseases as allergic rhinitis, bronchial asthma, anaphylaxis, atopic and contact dermatitis, chronic urticaria, and hypersensitivity pneumonitis. By releasing a variety of chemical mediators, they could also play a role in the pathophysiology of a wide range of inflammatory disorders of the joints, and of intestine, lung, coronary, and myocardial diseases. Although these two cell types are similar in several aspects, striking differences have also been observed. Moreover, human mast cells from different anatomical sites and within an individual tissue synthesize different mediators and have different release mechanisms. The recent advent of techniques that yield highly purified basophils and mast cells from diverse tissues will probably lead to major advancements in understanding the biochemical and pharmacological mechanisms that control the release process of these cells. The release of mediators from these cells is also controlled by a series of largely undefined biochemical steps that represent the basis of the concept of basophil and mast cell releasability. Alterations of basophil or mast cell releasability have already been detected in patients with allergic rhinitis, bronchial asthma, atopic dermatitis, and chronic urticaria. Taken together, these findings demonstrate that basophils, mast cells, and their chemical mediators play a pivotal role in several inflammatory disorders.
Animals↗
Successful endoscopic treatment of GI-tract fistulas with a fast-hardening amino acid solution.
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Adult↗
IgG anti-IgE from atopic dermatitis induces mediator release from basophils and mast cells.
IgG antibodies containing anti-IgE activity isolated from a patient with atopic dermatitis (H-aIgE) induced mediator release from human basophils and mast cells isolated from skin and lung tissues. The release of histamine was calcium- and temperature-dependent and did not involve cytotoxicity. There was an excellent correlation (r = 0.88; p less than 0.001) between the maximum percent histamine release from human basophils induced by rabbit anti-IgE (R-aIgE) and H-aIgE. H-aIgE was approximately 30 times more potent than R-aIgE in inducing mediator release from human basophils, skin, and lung mast cells. H-aIgE specifically desensitized human basophils to a subsequent challenge with both H-aIgE and R-aIgE. Lactic acid removal of IgE from human basophils blocked the releasing activity of both R-aIgE and H-aIgE. Passive sensitization with hyperimmune sera or purified IgE myeloma restored the response of basophils to both R-aIgE and H-aIgE. IgE purified from three different myeloma patients concentration-dependently blocked the histamine releasing activity of both R-aIgE and H-aIgE.
Adolescent↗
Inhibition of histamine and prostaglandin D2 release from human lung mast cells by ciclosporin A.
Cyclosporin A (CsA) is now widely used in the prevention/treatment of graft rejection and in the treatment of some human inflammatory diseases. We studied the effect of CsA on the release of chemical mediators from human lung mast cells in vitro. CsA (0.03-3 micrograms/ml) inhibited the release of histamine and prostaglandin D2 induced by anti-IgE from lung mast cells. CsA-induced inhibition of mediator release was not abolished by washing the cells before stimulation and it was not affected by the degree of purity of mast cell preparations. Our results indicate that CsA, in pharmacological concentrations, is a rapid and irreversible inhibitor of the release of preformed and de novo synthesized mediators from human lung mast cells. These findings might explain, at least in part, some of the therapeutic actions of CsA in vivo.
Antibodies, Anti-Idiotypic↗