1. 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.
- Author
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Boilard E and Surette ME
- Subjects
- Apoptosis drug effects, Arachidonic Acids pharmacology, CD3 Complex immunology, Cell Division, Cells, Cultured, Enzyme Inhibitors pharmacology, Humans, Imidazoles pharmacology, Interleukin-2 pharmacology, Kinetics, Lymphocyte Activation drug effects, Naphthalenes pharmacology, Oleic Acid metabolism, Organophosphorus Compounds pharmacology, Phosphodiesterase Inhibitors pharmacology, Phospholipases A metabolism, Phospholipases A2, Pyrones pharmacology, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Thymidine metabolism, Acyltransferases antagonists & inhibitors, Apoptosis physiology, Arachidonic Acid metabolism, Concanavalin A pharmacology, Lymphocyte Activation physiology, Muromonab-CD3 pharmacology, Organophosphonates, Phospholipids metabolism, T-Lymphocytes immunology
- Abstract
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. more...
- Published
- 2001
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