Reversal of lovastatin‐mediated inhibition of natural killer cell cytotoxicity by interleukin 2

The activation of human natural killer (NK) cell cytotoxicity by interleukin 2 (IL‐2) is well established, although the biochemical mechanisms ofthis stimulation have not yet been fully delineated. Earlier, we reported that treatment of NK cells with an inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase such as compactin or lovastatin significantly abrogates the in vitro killing of a susceptible human erythroleukemic cell line and that this inhibition can be completely reversed by 2 hr of exposure to mevalonate (J. Cell. Physiology 139:550–557, 1989). We report here that 24 hr of treatment with IL‐2 also reverses lovastatin inhibition of NK cell function. In addition to natural cytotoxicity, IL‐2 also restores chemotactic and antibody dependent cellular cytotoxicity functions to lovastatin‐treated cells. IL‐2 does not stimulate proliferation of these cells during this time period, nor does it affect the phenotypic composition of the NK cell preparations. Although IL‐2 was able to reverse the lovastatin‐mediated inhibition of every cell function we examined, it had no effect on the inhibition of cholesterol biosynthesis as measured by [ 3 H]acetate incorporation into non‐saponifiable lipids, nor did it stimulate HMG CoA reductase activity. These findings support the hypothesis that there is a non‐sterol isoprenoid product which is required for NK cell cytotoxicity and chemotaxis. In addition, the data suggest that IL‐2 stimulation of NK cells proceeds by an isoprenoid‐independent pathway.