Clofazimine and B669 inhibit the proliferative responses and Na+, K(+)-adenosine triphosphatase activity of human lymphocytes by a lysophospholipid-dependent mechanism.
The relationship between the phospholipase-stimulating and immunosuppressive properties of the riminophenazine anti-mycobacterial agent clofazimine and its experimental analogue, B669, has been investigated in vitro. At concentrations of 0.6 microM and upwards, both riminophenazines, particularly B669, caused dose-related inhibition of mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear leucocytes (MNL), while in short-term assays both agents increased the release of lysophosphatidylcholine (LPC) and arachidonic acid from these cells. Arachidonate per se at a concentration of 20 microM did not affect mitogen-activated lymphocyte proliferation, while cyclooxygenase and 5'-lipoxygenase inhibitors, as well as water- and lipid-soluble oxidant-scavengers and anti-oxidant enzymes, failed to protect the cells against the anti-proliferative effects of clofazimine and B669. However, LPC caused dose-related inhibition of lymphocyte proliferation. Moreover, co-incubation of NML with alpha-tocopherol (vitamin E), a lysophospholipid complex-forming agent, or with lysophospholipase, protected the cells against clofazimine and B669, as well as against LPC. Na+, K(+)-adenosine triphosphatase was identified as the primary target of riminophenazine/LPC-mediated inhibition of lymphocyte proliferation. Excessive release of anti-proliferative lysophospholipids during clofazimine or B669 treatment of mitogen- or antigen-activated lymphocytes is the probable biochemical mechanism of the immunosuppressive activity of these agents.
Anderson
R
R
Department of Immunology, University of Pretoria, Republic of South Africa.
Smit
M J
MJ
D000890:Anti-Infective Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002991:Clofazimine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008245:Lysophospholipase / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D014316:Tritium; D014810:Vitamin E / Q000737:chemistry
D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D014316:Tritium; D014810:Vitamin E; D016718:Arachidonic Acid; C030428:B 669; D002991:Clofazimine; D010741:Phospholipases A; D008245:Lysophospholipase; D000254:Sodium-Potassium-Exchanging ATPase