Effects of changes in membrane potential on the cyclosporin-induced inhibition of T-cell proliferation.
Cyclosporin A (CsA) exerts its major immunosuppressive effect by inhibition of T-lymphocyte proliferation. The precise mechanism and target of its action has not yet been completely identified. CsA is also known to induce a rapid membrane depolarization in T lymphocytes. We have tested the role of CsA-dependent depolarization in the inhibition of T-cell proliferation by the drug. In these studies, induced membrane depolarization (in the presence of gramicidin or by replacing the Na+ content of the medium with K+) or hyperpolarization (in the presence of valinomycin) had no influence on the induction of T-cell competence by phorbol dibutyrate/ionomycin or by submitogenic concentrations of PHA, a target for CsA immunosuppression. However, regardless of the state of membrane potential during the induction of T-cell competence, the inhibition by CsA was the same as seen in normally polarized cells. We conclude that the depolarization induced by CsA is not a critical element in its inhibitory effect on T-cell proliferation.
Tordai
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Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
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Gelfand
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D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D014634:Valinomycin / Q000494:pharmacology
D010835:Phytohemagglutinins; D014634:Valinomycin; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D016572:Cyclosporine