Enhancement of Murine Lymphokine-activated Killer Cell Activity by Retinole Acid1

Since retinÃ3las have been suggested to be capable of potentiating immunity, the present study was undertaken to determine the effect, if any, on lymphokine-activated killer (LAK) cell activity by retinoic acid, an active metabolite of vitamin A and a differentiation enhancer. Retinoic acid alone was shown to induce no cytotoxicity generated from nylon wool-treated nonadherent murine (BALB/c) splenocytes against natural killer-resistant, LAK-sensitive syngeneic target tumor cells. When com bined with human recombinant interleukin-2 (IL-2), retinoic acid aug mented LAK cell activity in both a doseand time-dependent manner. The augmentation was detected at IO"10M retinoic acid and reached the maximum at IO M, a >200% increase in lytic activity. Kinetic study revealed that retinoic acid augmented significantly LAK cell activity when incubated in IL-2-containing culture as short as for 6 h before cytotoxicity was measured. The removal of retinoic acid from culture resulted in the loss of the augmentation. Retinoic acid was found to augment LAK cell activity in a wide range of IL-2 concentrations (75012,000 11 ml ), even at 6,000 11 /nil where the maximal induction of LAK cell activity had been reached. No phenotype or proliferation of LAK cells was altered by the addition of retinoic acid to IL-2-containing culture. However, cellular serine protease activity, measured as N-abenzyloxycarbonyl-i.-lysine thiobenzyl-esterase, in LAK cells was in creased by retinoic acid also in a doseand time-dependent manner. The increase in LAK cellular serine protease activity was significantly corre lated with that of augmented LAK cell activity. Overall these results demonstrated that IL-2-induced LAK cell activity was enhanced by retinoic acid and that the augmentation may be mediated by means of enhanced expression of cellular serine protease activity. This study also suggests that, in addition to its use in chemoprevention of cancer, retinoic acid is of potential in adoptive immunotherapy.