Energy levels in resting and mitogen-stimulated human lymphocytes during treatment with FK506 or cyclosporin A in vitro.
By employing microcalorimetry to assess overall metabolic activity in combination with other assays for specific metabolic events, we have investigated the influence of cyclosporin A and FK506 on the metabolic status of resting and mitogen-stimulated human peripheral lymphocytes. Both cyclosporin A and FK506 significantly reduced heat output from resting lymphocytes. This reduction could not be correlated with effects on DNA synthesis, lactate production, ATP levels or mitochondrial uptake of Rhodamine 123. These two drugs also potently reduced the increase in heat output seen during mitogen stimulation of lymphocytes. Both cyclosporin A and FK506 also prevented the increase in DNA synthesis, lactate production and ATP levels seen in response to mitogen stimulation. The increase in mitochondrial uptake of Rhodamine 123 during blastoid transformation was significantly reduced only by cyclosporin A. We ascribe the major part of the effects of these compounds to inhibition of the glycolytic pathway in both resting and mitogen-stimulated lymphocytes. These results indicate that the immunosuppressants cyclosporin A and FK506 exert other effects on lymphocytes than their well-established inhibitory action on calcineurin.
Karlsson
H
H
Department of Medical Microbiology, Lund University, Sweden. hakan@tuborg.biokemi.su.se
DePierre
J W
JW
Nässberger
L
L
D000255:Adenosine Triphosphate / Q000378:metabolism; D002151:Calorimetry; D002470:Cell Survival; D002478:Cells, Cultured; D003208:Concanavalin A; D016572:Cyclosporine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004734:Energy Metabolism / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007425:Intracellular Membranes / Q000502:physiology; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D007166:Immunosuppressive Agents; D007773:Lactates; D003208:Concanavalin A; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D004247:DNA; D013936:Thymidine; D016559:Tacrolimus