Lysophospholipid-mediated inhibition of Na+,K(+)-adenosine triphosphatase is a possible mechanism of immunosuppressive activity of cyclosporin A.
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.
Anderson
R
R
Department of Immunology, University of Pretoria, Republic of South Africa.
Smit
M J
MJ
Van Rensburg
C E
CE
D000328:Adult; D016718:Arachidonic Acid / Q000096:biosynthesis; D016572:Cyclosporine / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008246:Lysophospholipids / Q000096:biosynthesis / Q000502:physiology*; D010740:Phospholipases / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology
D008246:Lysophospholipids; D014810:Vitamin E; D016718:Arachidonic Acid; D016572:Cyclosporine; D010740:Phospholipases; D000254:Sodium-Potassium-Exchanging ATPase; D015232:Dinoprostone