The immunosuppressive activities of different cyclosporins are correlated to inhibition of the early membrane phospholipid metabolism in activated lymphocytes.
Recently, it could be shown that Cyclosporin A (CsA) inhibited the activation of T and B lymphocytes by interfering with an early step of the activation, namely the stimulation of the plasma membrane-bound lysophosphatide acyltransferase. In this report, we compared three CsA-derivatives, Dihydro-Cyclosporin C (Dihydro-CsC), "C9-O-Acetyl"-CsA (CsAAC), Cyclosporin H (CsH), regarding the inhibition of proliferation and the interference with the activation of the phospholipid metabolism. At concentrations below 1 microgram/ml, CsAAC and CsH had no effect on any parameter measured. Dihydro-CsC, however, closely resembled CsA: it inhibited the induction of DNA- and RNA-synthesis in T and B lymphocytes from mesenteric lymph nodes of rabbits. Similar to CsA, Dihydro-CsC also interfered with the enhanced incorporation of arachidonic acid into plasma membrane phospholipids by inhibiting the activation of the lysophosphatide acyltransferase. The close correlation between inhibition of proliferation and interferences with the phospholipid metabolism of the plasma membrane suggested that Dihydro-CsC as well as CsA interfered with an early step of lymphocyte activation at the level of the plasma membrane.
Kroggel
R
R
Department of Pharmacology and Toxicology, Medical School, Hannover, Federal Republic of Germany.
Goppelt-Strübe
M
M
Martin
M
M
Resch
K
K
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011817:Rabbits
D003524:Cyclosporins; D008563:Membrane Lipids; D010743:Phospholipids; D008243:1-Acylglycerophosphocholine O-Acyltransferase