PT - JOURNAL ARTICLE AU - R Anderson AU - M J Smit AU - C E Van Rensburg TI - Lysophospholipid-mediated inhibition of Na+,K(+)-adenosine triphosphatase is a possible mechanism of immunosuppressive activity of cyclosporin A. DP - 1993 Sep 01 TA - Molecular Pharmacology PG - 605--614 VI - 44 IP - 3 4099 - http://molpharm.aspetjournals.org/content/44/3/605.short 4100 - http://molpharm.aspetjournals.org/content/44/3/605.full SO - Mol Pharmacol1993 Sep 01; 44 AB - The relationship between the phospholipase-stimulating and immunosuppressive properties of cyclosporin A (CsA) has been investigated in vitro. At concentrations of 0.025 microM and upwards, CsA caused dose-related inhibition of both mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear leukocytes (MNL), which was associated with a time- and dose-related enhancement of the generation of lysophosphatidylcholine (LPC), arachidonic acid, and prostaglandin E2 from mitogen-stimulated cells. Arachidonate alone, at concentrations of up to 20 microM, did not affect lymphocyte activation, whereas cyclooxygenase and 5'-lipoxygenase inhibitors failed to protect the cells against the antiproliferative effects of CsA. However, LPC caused dose-related inhibition of MNL proliferation. Moreover, coincubation of MNL with alpha-tocopherol, a lysophospholipid-complexing agent, or with lysophospholipase protected the cells against CsA, as well as against LPC. The Na+,K(+)-ATPase activity of mitogen-activated lymphocytes was also inhibited by CsA, whereas inclusion of alpha-tocopherol or lysophospholipase protected this enzyme. Excessive production of lysophospholipids and consequent inhibition of Na+,K(+)-ATPase during CsA treatment of mitogen- or antigen-activated lymphocytes is a possible biochemical mechanism of the immunosuppressive activity of this agent.