Biochemical characterization of the inhibitory effect of CsA on cytolytic T lymphocyte effector functions.
We have examined the effects of cyclosporine A (CsA) on a number of CTL effector functions. CsA partially inhibited the CTL-mediated lysis of Ag-bearing target cells. Both target cell- and anti-TCR mAb-induced granule exocytosis were markedly inhibited by CsA. In addition, marked inhibition of PMA and calcium ionophore (A23187) induced granule exocytosis was produced by CsA suggesting that the inhibitory effects of CsA on granule exocytosis involve biochemical events after protein kinase C activation and increases in intracellular free Ca2+. CsA had no inhibitory effects on TCR-mediated phosphatidylinositol metabolism. The inhibitory effects of CsA were not mediated by the cAMP-dependent protein kinase inhibitory pathway and no effect of CsA on the Ca2+-induced binding of calmodulin to calmodulin-binding proteins could be demonstrated. CsA was also a potent inhibitor of IgE receptor-mediated exocytosis in rat basophil leukemia cells. CsA had no effect on receptor-mediated phosphatidylinositol hydrolysis; 400 ng/ml CsA resulted in a 90% inhibition of serotonin release but had no effect on phosphatidylinositol hydrolysis. These results indicate that CsA may inhibit some common event in Ca2+-dependent secretory cells. Taken together, these results suggest that CsA does not inhibit signal transduction but rather interferes with the biochemical events in the later stages of Ca2+-dependent reactions that follow the binding of calmodulin to cytoskeletal or cytoplasmic calmodulin binding proteins.
Trenn
G
G
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20912.
Taffs
R
R
Hohman
R
R
Kincaid
R
R
Shevach
E M
EM
Sitkovsky
M
M
D000818:Animals; D000001:Calcimycin; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005089:Exocytosis / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate
D002148:Calmodulin-Binding Proteins; D003524:Cyclosporins; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D011948:Receptors, Antigen, T-Cell; D000001:Calcimycin; D013755:Tetradecanoylphorbol Acetate