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.
Cirillo
R
R
Department of Medicine, University of Naples Federico II, Second School of Medicine, Italy.
Triggiani
M
M
Siri
L
L
Ciccarelli
A
A
Pettit
G R
GR
Condorelli
M
M
Marone
G
G
D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D001491:Basophils / Q000187:drug effects*; D054713:Bryostatins; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D003524:Cyclosporins / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D019696:Peptidylprolyl Isomerase; D013189:SRS-A / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D054713:Bryostatins; D002352:Carrier Proteins; D003524:Cyclosporins; D007783:Lactones; D018942:Macrolides; D013189:SRS-A; D007073:Immunoglobulin E; D000001:Calcimycin; C046785:bryostatin 1; D019696:Peptidylprolyl Isomerase; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium