ANTIOXIDANTS IMPAIR THE COUPLING OF CELL-SURFACE LIGAND RECEPTORS TO THE INOSITOL LIPID SIGNALING PATHWAY IN HUMAN T-LYMPHOCYTES BUT NOT INJURKAT T-LYMPHOBLASTIC LEUKEMIA-CELLS - EVIDENCE THAT LEUKOTRIENES ARE NOT INVOLVED IN THE COUPLING MECHANISM

Ligands including phytohaemagglutinin (PHA) and anti-CD3 monoclonal an tibodies trigger the generation of inositol lipid-de-rived second mess engers following their binding to cell-surface structures of human T l ymphoid cells. Previous evidence has suggested that the generation of leukotrienes may play an intermediary role in coupling the ligation of T lymphoid cell-surface structures to the inositol lipid signalling s ystem in these cells (A.R. Mire-Sluis et al. (1989) FEBS Lett. 258, 84 -88). Here we have studied the actions of two novel selective leukotri ene biosynthesis inhibitors, MK 886 and BW A4C and of two general lipi d soluble antioxidants, butylated hydroxytoluene (BHT) and butylated h ydroxyanisole (BHA) on this pathway. Neither MK 886 nor BW A4C abrogat ed stimulation of inositol lipid breakdown following PHA or anti CD3 t reatment of T lymphocytes. By contrast, this pathway was inhibited by BHT and BHA. These observations, together with our failure to demonstr ate the generation of lipoxygenase products following PHA stimulation of T lymphocytes, suggests that an antioxidant-sensitive step other th an the generation of leukotrienes plays a critical role in coupling ce ll-surface receptors to the inositol lipid signalling system in these cells. By contrast none of these inhibitors abrogated ligand-stimulate d inositol lipid signalling in Jurkat T acute lymphoblastic leukaemia cells. These results suggest a heterogeneity in the organization of th e signal transduction machinery in lymphoid cells at different stages of differentiation.