Opposing effects of rapamycin and cyclosporin A on activation-induced Ca(2+) release.
Insofar as Ca(2+) plays a major role in T cell activation, we investigated the effect of the immunosuppressants cyclosporin A and rapamycin on T cell proliferation and on the activation-induced increase in [Ca(2+)](i). Both cyclosporin A and rapamycin inhibited mitogen (concanavalin A and phytohemagglutinin) and ionomycin+phorbol myristate acetate (PMA)-driven T cell proliferation (Ca(2+)-dependent). However, only rapamycin suppressed T cell proliferation stimulated by anti-CD28 antibody (Ab)+PMA, and recombinant interleukin-6-stimulated proliferation of the interleukin-6 dependent B9 cells (Ca(2+)-independent). These differences were associated with a different effect of both drugs on Ca(2+) release, as cyclosporin A attenuated while rapamycin augmented the mitogen-induced elevation in [Ca(2+)](i). Collectively, this supports the notion that Ca(2+) is required in early stages of T cell activation, and that cyclosporin A blocked only Ca(2+)-dependent while rapamycin blocked both Ca(2+)-dependent and -independent events of T cell activation.
Almawi
W Y
WY
Molecular Biology Section, Department of Laboratory Medicine, St. Georges Hospital, Beirut, Lebanon. wyalmawi@aub.edu.lb
Assi
J W
JW
Chudzik
D M
DM
Lazarovits
A I
AI
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D002614:Chelating Agents; D007166:Immunosuppressive Agents; D003208:Concanavalin A; D004533:Egtazic Acid; D015759:Ionomycin; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D020123:Sirolimus