LIPOXYGENASE INHIBITORS COUNTERACT PROTEIN-KINASE-C MEDIATED EVENTS IN HUMAN T-LYMPHOCYTE PROLIFERATION

Four structurally unrelated inhibitors of lipoxygenase (LO), i.e. nord ihydroguaiaretic acid (NDGA), Esculetin, AA861 and 5,8,11,14-eicosatet raynoic acid (ETYA) suppressed mitogen induced proliferation of human peripheral blood lymphocytes in a dose-dependent manner. The degree of suppression was influenced by the type of the mitogenic stimulus. Rec eptor mediated stimulation, i.e. through phytohemagglutinin or the ant i-CD3 antibody OKT3, was overall less susceptible, whereas proliferati on initiated by direct activation of protein kinase C (PKC), i.e. thro ugh phorbol myristate acetate or indolactam V, was profoundly suppress ed (up to 90%). The effect of the LO inhibitors was not due to non-spe cific interference with intracellular radical intermediates, because A A861 and ETYA showed no radical scavenging activity. Two PKC inhibitor s, H-7 and H-8, similarly suppressed lymphocyte proliferation and show ed essentially the same suppressive pattern as LO inhibitors. The resu lts clearly indicate that LO product(s) participate in signal transduc tion mechanisms in T lymphocytes, possibly via stimulation of PKC acti vity and cell proliferation. (C) 1997 International Society for Immuno pharmacology.