Cyclosporin A inhibits degranulation of rat basophilic leukemia cells and human basophils. Inhibition of mediator release without affecting PI hydrolysis or Ca2+ fluxes.
Cyclosporin A (CSA) inhibits IgE receptor-mediated exocytosis from rat basophilic leukemia (RBL) cells and human peripheral blood basophils in a dose-dependent manner over the therapeutic range of CSA concentrations achieved in vivo. Half-maximal inhibition was observed at 0.2 micrograms/ml CSA. The effect of CSA on several biochemical parameters involved in receptor-mediated activation of RBL cells was examined. Maximum inhibition of secretion occurred when CSA was added 5 min before activation, and inhibition was nearly maximum when the drug was added 2 min before the cells were triggered. The same results were observed when RBL cells were stimulated with A23187, a calcium ionophore. These results suggest a mechanism other than inhibition of protein synthesis is involved. Inhibition by CSA of release by either secretagogue persisted, even if CSA was removed from the buffer before the cells were triggered. No inhibition was observed of either receptor-mediated phosphatidylinositol hydrolysis, 45Ca2+ uptake, or the rise in the intracellular concentration of free Ca2+ under the same conditions that produced greater than 80% inhibition of serotonin release. These results demonstrate that the early events in signal transduction are not affected, and suggest that the intracellular target for CSA participates in a later stage of exocytosis. Furthermore, the data suggest that CSA suppresses cells other than T lymphocytes and predict that patients on CSA therapy may have altered response to allergens.
Allergic Diseases Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
T
T
Hultsch
J L
JL
Rodriguez
M A
MA
Kaliner
R J
RJ
Hohman
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001491:Basophils / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D003524:Cyclosporins / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000502:physiology; D066298:In Vitro Techniques; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011961:Receptors, Fc / Q000502:physiology*; D017455:Receptors, IgE; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000944:Antigens, Differentiation, B-Lymphocyte; D003524:Cyclosporins; D010716:Phosphatidylinositols; D011961:Receptors, Fc; D017455:Receptors, IgE; D012701:Serotonin; D007073:Immunoglobulin E; D000001:Calcimycin; D002118:Calcium