Lipoxygenase inhibitors counteract protein kinase C mediated events in human T lymphocyte proliferation

Four structurally unrelated inhibitors of lipoxygenase (LO), i.e. nordihydroguaiaretic acid (NDGA), Esculetin, AA861 and 5,8,11,14-eicosatetraynoic 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. Receptor mediated stimulation, i.e. through phytohemagglutinin or the anti-CD3 antibody OKT3, was overall less susceptible, whereas proliferation initiated by direct activation of protein kinase C (PKC), i.e. through phorbol myristate acetate or indolactam V, was profoundly suppressed (up to 90%). The effect of the LO inhibitors was not due to non-specific interference with intracellular radical intermediates, because AA861 and ETYA showed no radical scavenging activity. Two PKC inhibitors, H-7 and H-8, similarly suppressed lymphocyte proliferation and showed essentially the same suppressive pattern as LO inhibitors. The results clearly indicate that LO product(s) participate in signal transduction mechanisms in T lymphocytes, possibly via stimulation of PKC activity and cell proliferation.