Anti-CD3 and concanavalin A-induced human T cell proliferation is associated with an increased rate of arachidonate-phospholipid remodeling. Lack of involvement of group IV and group VI phospholipase A2 in remodeling and increased susceptibility of proliferating T cells to CoA-independent transacyclase inhibitor-induced apoptosis.
In this study arachidonate-phospholipid remodeling was investigated in resting and proliferating human T lymphocytes. Lymphocytes induced to proliferate with either the mitogen concanavalin A or with anti-CD3 (OKT3) in combination with interleukin 2 (OKT3/IL-2) showed a greatly accelerated rate of [3H]arachidonate-phospholipid remodeling compared with resting lymphocytes or with lymphocytes stimulated with OKT3 or IL-2 alone. The concanavalin A-stimulated cells showed a 2-fold increase in the specific activity of CoA-independent transacylase compared with unstimulated cells, indicating that this enzyme is inducible. Stimulation with OKT3 resulted in greatly increased quantities of the group VI calcium-independent phospholipase A2 but not of the quantity of group IV cytosolic phospholipase A2. However, group IV phospholipase A2 became phosphorylated in OKT3-stimulated cells, as determined by decreased electrophoretic mobility. Incubation of cells with the group VI phospholipase A2 inhibitor, bromoenol lactone, or the dual group IV/group VI phospholipase A2 inhibitor, methyl arachidonyl fluorophosphonate, did not block arachidonate-phospholipid remodeling resting or proliferating T cells, suggesting that these phospholipases A2 were not involved in arachidonate-phospholipid remodeling. The incubation of nonproliferating human lymphocytes with inhibitors of CoA-independent transacylase had little impact on cell survival. In contrast, OKT3/IL-2-stimulated T lymphocytes were very sensitive to apoptosis induced by CoA-independent transacylase inhibitors. Altogether these results indicate that increased arachidonate-phospholipid remodeling is associated with T cell proliferation and that CoA-independent transacylase may be a novel therapeutic target for proliferative disorders.
Boilard
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Centre de Recherche en Rhumatologie et Immunologie, and Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada.
Surette
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ME
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D016853:Muromonab-CD3 / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D019301:Oleic Acid / Q000378:metabolism; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D001095:Arachidonic Acids; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D016853:Muromonab-CD3; D009281:Naphthalenes; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010726:Phosphodiesterase Inhibitors; D010743:Phospholipids; D011753:Pyrones; C093303:SK&F 98625; C104810:methyl arachidonylfluorophosphonate; D003208:Concanavalin A; D016718:Arachidonic Acid; D019301:Oleic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D000217:Acyltransferases; D010741:Phospholipases A; D054467:Phospholipases A2; D013936:Thymidine