Cyclosporin immunosuppression mediated by calcium/sodium imbalance.
Cyclosporin immunosuppression is mediated by a calcium/sodium excess during G0 which inhibits further cell cycle progression. The consequences of cyclosporin on electrolyte content were measured in T-lymphocytes stimulated with concanavalin A. Cyclosporin caused an excessive accumulation of extracellular calcium for the first 4 h of lectin stimulation. The nonpermissive calcium content resulted from a reduction in the rate of calcium efflux from the cell. Because cyclosporin did not affect calcium translocation via ATPase but did permit excessive amounts of sodium to enter the resting cell we hypothesized that the calcium excess is caused by a shut-down of the Ca2+/Na+ antiport during the first hours of lectin stimulation. The subsequent normalization of calcium content is coincident with the onset of mRNA synthesis, which suggests development of compensatory mechanisms to alleviate the calcium burden. The G0 calcium excess did not affect other transductive events such as ligand recognition, phosphatidyl inositol metabolism, or adenylate cyclase activation. This study points to the causative mechanism of cyclosporin immunosuppression and emphasized the dynamic role of ions as modulators of normal cell proliferation.
Kimball
P M
PM
Department of Surgery, University of Texas Health Science Center, Houston 77030.
Sell
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003208:Concanavalin A; D000242:Cyclic AMP / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger; D014883:Water-Electrolyte Imbalance / Q000276:immunology*
D002352:Carrier Proteins; D003524:Cyclosporins; D008565:Membrane Proteins; D010716:Phosphatidylinositols; D019831:Sodium-Calcium Exchanger; D003208:Concanavalin A; D012964:Sodium; D000242:Cyclic AMP; D002118:Calcium