Protein kinase activation and the immunosuppressant cyclosporine.
Cyclosporine (CsA), a potent immunosuppressant for the prevention of transplant rejection, modulates T lymphocyte activation by blocking antigen stimulation and the production of interleukin-2. The mode of action by which CsA generates this immunosuppressive effect is unknown. We have studied two early intracellular enzymes associated with mitogen activation. They include calcium/phospholipid-dependent protein kinase (C-kinase) and cAMP-dependent protein kinase (cAMPd PK). Changes in protein kinase activation were correlated with the immunosuppression of polyamine and DNA synthesis measured by ornithine decarboxylase (ODC) induction and 3H-thymidine incorporation, respectively. These studies utilized murine T cell tumor lines sensitive to the effects of CsA. Similar to the mitogen activation of human peripheral blood lymphocytes, CsA was capable of inhibiting the induction of ODC and 3H-thymidine uptake of T cell tumor lines cultured with either fresh serum or mitogen. In contrast, C-kinase and cAMPd PK activation stimulated by the addition of fresh serum was not affected by CsA. Further, CsA did not inhibit the direct activation of C-kinase with phorbol esters or the activation of cAMPd PK with exogenous cAMP. We conclude that CsA does not affect the activation of either C-kinase or cAMPd PK in T cell tumor lines when activated by either fresh serum or when stimulated with chemical agents. The suppression of ODC induction and 3H-thymidine incorporation associated with CsA treatment cannot be accounted for with changes in C-kinase and cAMPd PK activation.
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D007938:Leukemia / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D011493:Protein Kinase C / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003524:Cyclosporins; D000242:Cyclic AMP; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate