Mechanisms of IL2 production impairment by lipoxygenase inhibitors in activated Jurkat cells.
We investigated the mechanisms by which lipoxygenase (LO) inhibitors decrease interleukin-2 (IL-2) production in Jurkat cells. We demonstrate that the inhibition, linked to blockade of the [Ca2+]i rise involving T cell receptor (TCR) triggering, resulted from the action of these compounds on the signal transduction pathway, upstream from inositol triphosphate synthesis. IL2 secretion induced by phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187, which bypasses the breakdown of inositol phospholipids induced by the ligand-receptor interaction, was still suppressed by LO inhibitors which implies that these drugs also have an inhibitory effect on other target(s). None of the three protein kinase C (PKC)-dependent events investigated was affected in Jurkat cells stimulated in the presence of LO inhibitors. Furthermore, these compounds did not inhibit IL2 production in PMA-treated Jurkat cells cultured with vanadate, which mimics the tyrosine kinase activation pathway and induces IL2 secretion. This suggests that in addition to their effect on the phosphatidylinositol diphosphate pathway-dependent [Ca2+]i rise, LO inhibitors might affect the tyrosine kinase pathway in TCR-activated Jurkat cells, but probably not the PKC-dependent pathway. These results are consistent with a role for LO metabolite(s) in signal transduction pathways.
Dornand
J
J
INSERM U 65, U.S.T.L., Montpellier, France.
Gerber
M
M
D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017252:CD3 Complex; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis*; D007700:Kinetics; D015289:Leukotrienes / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D009637:Masoprocol / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D010738:Type C Phospholipases / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D006893:Hydroxyeicosatetraenoic Acids; D007376:Interleukin-2; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D009637:Masoprocol; D011493:Protein Kinase C; D010738:Type C Phospholipases; D004121:Dimethyl Sulfoxide