Comparison of the immunosuppressive effects of cyclosporine, lipid-soluble anesthetics, and calmodulin antagonists. Response to exogenous interleukin 2.
The purpose of these investigations was to compare the immunosuppressive mechanism of cyclosporine (CsA) with those of lipid-soluble local anesthetics and calmodulin antagonists. Chlorpromazine (CPZ) and pentobarbital (PB) both inhibit lymphocyte activation by attenuating sodium and potassium ion potentials. CPZ and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7) can also block calcium-dependent activation processes by inhibition of calmodulin and protein kinase C. All four compounds were found to suppress human and murine lymphoproliferation to both alloantigen or mitogen in a dose-dependent and saturable manner. Exogenous interleukin-2 (IL-2) restored mitogenic responsiveness to cultures suppressed using W-7 and CsA, but not to lymphocytes suppressed with either CPZ or PB. Cytofluorographic analysis revealed that the degree of suppression in drug-treated lymphocytes was significantly correlated with the surface expression of receptors for transferrin and interleukin-2. Inhibition of IL-2 activation by PB was demonstrated to result from a blockade of the mitogenic growth factor signal using the IL-2-dependent cell line HT-2. Thus, the mechanism of action of cyclosporine can be differentiated from those of anesthetic immunosuppressants at the level of responsiveness to interleukin-2. The data support the hypothesis that cyclosporine may be an antagonist of calmodulin that selectively blocks early events in T lymphocyte activation leading to IL-2 synthesis, but does not inhibit the expression or function of the IL-2 receptor.
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000440:Butanols / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002746:Chlorpromazine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D010424:Pentobarbital / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000378:metabolism; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin / Q000378:metabolism; D012995:Solubility; D013449:Sulfonamides / Q000494:pharmacology
D000777:Anesthetics; D000440:Butanols; D002147:Calmodulin; D003524:Cyclosporins; D007376:Interleukin-2; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D013449:Sulfonamides; D000431:Ethanol; C017967:W 7; D011493:Protein Kinase C; D010424:Pentobarbital; D002746:Chlorpromazine