THIOL-BEARING COMPOUNDS SELECTIVELY INHIBIT PROTEIN-KINASE C-DEPENDENT OXIDATIVE EVENTS AND PROLIFERATION IN HUMAN T-CELLS

The aminothiol cysteamine at 10(-5) to 10(-4) M concentrations inhibited both the proliferation of mitogenically stimulated human peripheral mononuclear cells and the phorbol myristate acetate-mediated oxidation of 2',7'-dichlorofluorescin within these cells. Both 2',7'-dichlorofluorescin oxidation and the proliferative response were maximally sensitive to cysteamine-induced inhibition during the first 2 h of mitogenic stimulation. This period of sensitivity indicates that cysteamine preferentially arrests cells transiting from G(0) to G(1) and is the first such demonstration, of an early cell cycle site of arrest for this compound. 2,3-Dimercapto-1-propane-sulfonic acid and WR 1065 were found to be more effective than cysteamine in attenuating T cell replication but not N-acetylcysteine. Aminothiols preferentially inhibited the intracellular oxidation of 2',7'-dichlorofluorescin, rather than the activity of protein kinase C, which initiates the oxidation, indicating that oxidative events are one of a number of crucial and independent events required for the successful transition through G(0)-G(1). Since aminothiols affect both lectin and PMA/ionomycin-directed proliferation, these aminothiol-sensitive events may serve to integrate and regulate common pathways in T cell activation.