THE ROLE OF PHORBOL ESTER-SENSITIVE PROTEIN-KINASE-C ISOFORMS IN LYMPHOKINE-ACTIVATED KILLER CELL-MEDIATED CYTOTOXICITY - DISSOCIATION BETWEEN PERFORIN-DEPENDENT AND FAS-DEPENDENT CYTOTOXICITY

Treatment of lymphokine-activated killer (LAK) cells with phorbol este r (PMA) caused the downmodulation of LAK activity concomitantly with t he inhibition of serine esterase (SE) release, which has been shown as a marker for perforin-dependent cell-mediated cytotoxicity. The reduc tion of perforin-dependent LAK activity by PMA-treatment appeared to b e due to the disappearance of PMA-sensitive protein kinase C (PKC) iso forms such as PKC alpha, gamma, epsilon, theta. In contrast, Fas-media ted LAK activity was refractory against PMA-induced downregulation. Tr eatment of LAK cells with PMA caused a disappearance of cytotoxicity a gainst Fas(-) L5178Y tumor cells, while cytotoxicity against Fas(+) tr ansfectants was not affected by PMA treatment. Moreover, Fas-mediated LAK activity of perforin-knockout mice was not inhibited by PMA treatm ent. These results clearly demonstrated that Fas-mediated cytotoxicity could be dissociated from perforin-mediated cytotoxicity by their dif ferent requirement of PMA-sensitive PKC isoforms. (C) 1997 Academic Pr ess.