Antioxidants impair the coupling of cell-surface ligand receptors to the inositol lipid signalling pathway in human T lymphocytes but not in Jurkat T lymphoblastic leukemia cells. Evidence that leukotrienes are not involved in the coupling mechanism.
Ligands including phytohaemagglutinin (PHA) and anti-CD3 monoclonal antibodies trigger the generation of inositol lipid-derived second messengers following their binding to cell-surface structures of human T lymphoid 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 system 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 leukotriene biosynthesis inhibitors, MK 886 and BW A4C and of two general lipid soluble antioxidants, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) on this pathway. Neither MK 886 nor BW A4C abrogated stimulation of inositol lipid breakdown following PHA or anti CD3 treatment of T lymphocytes. By contrast, this pathway was inhibited by BHT and BHA. These observations, together with our failure to demonstrate the generation of lipoxygenase products following PHA stimulation of T lymphocytes, suggests that an antioxidant-sensitive step other than the generation of leukotrienes plays a critical role in coupling cell-surface receptors to the inositol lipid signalling system in these cells. By contrast none of these inhibitors abrogated ligand-stimulated inositol lipid signalling in Jurkat T acute lymphoblastic leukaemia cells. These results suggest a heterogeneity in the organization of the signal transduction machinery in lymphoid cells at different stages of differentiation.
Department of Haematology, Royal Free Hospital School of Medicine, London, UK.
M A
MA
Khan
J Y
JY
Jeremy
T
T
Hallinan
J E
JE
Tateson
A V
AV
Hoffbrand
R G
RG
Wickremasinghe
D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects*; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D015289:Leukotrienes / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism*; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000945:Antigens, Differentiation, T-Lymphocyte; D000975:Antioxidants; D015289:Leukotrienes; D010716:Phosphatidylinositols; D016718:Arachidonic Acid; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C