Inhibition of T lymphocyte activation by cyclosporin A: interference with the early activation of plasma membrane phospholipid metabolism.
Rabbit lymph node and thymus lymphocytes were stimulated with concanavalin A (Con A). Cyclosporin A (CSA) inhibited in a dose-dependent way the induction of RNA and DNA synthesis; nearly complete inhibition was observed at a concentration of 200 ng/ml. Results of kinetic studies suggested that the immunosuppressive drug interfered with an early event occurring in activated lymphocytes. Among the earliest changes detectable in activated lymphocytes, the turnover of plasma membrane phospholipids is increased, predominantly of their fatty acid moieties, catalyzed by the membrane-bound lysophosphatide acyltransferase. CSA, at concentrations identical with those inhibiting macromolecular synthesis, also inhibited the Con A-stimulated specific increase in the incorporation of labeled fatty acids into plasma membrane phospholipids. When lymphocytes were stimulated with Con A for 1 hr, incorporation of labeled oleic acid and arachidonic acid approximately doubled in plasma membrane phospholipids. CSA at a concentration of 200 ng/ml prevented the elevated incorporation of labeled fatty acids into plasma membrane phospholipids of Con A-stimulated thymocytes. Concomitantly, the activation of lysolecithin acyltransferase, the key enzyme for the incorporation of long-chain fatty acids into phospholipids, was strongly inhibited. Up to high concentrations, CSA had no effect on the phospholipid metabolism of unstimulated lymphocytes. The results suggest that CSA inhibits the activation of T lymphocytes by interfering with the early activation of plasma membrane phospholipid metabolism.
M
M
Szamel
P
P
Berger
K
K
Resch
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D046911:Macromolecular Substances; D008563:Membrane Lipids / Q000378:metabolism*; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis; D011817:Rabbits; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000201:enzymology; D014529:Uridine / Q000378:metabolism
D001095:Arachidonic Acids; D003524:Cyclosporins; D046911:Macromolecular Substances; D008563:Membrane Lipids; D009829:Oleic Acids; D010743:Phospholipids; D003208:Concanavalin A; D016718:Arachidonic Acid; D019301:Oleic Acid; D012313:RNA; D004247:DNA; D008243:1-Acylglycerophosphocholine O-Acyltransferase; D014529:Uridine