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 of this 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 [3H]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.
Cutts
J L
JL
Department of Medicine, School of Medicine, University of New Mexico, Albuquerque 87131.
Bankhurst
A D
AD
D000085:Acetates / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008148:Lovastatin / Q000037:antagonists & inhibitors*; D008358:Mannose / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D000085:Acetates; D007376:Interleukin-2; D014316:Tritium; D002784:Cholesterol; D008148:Lovastatin; D008358:Mannose; D008798:Mevalonic Acid; D013936:Thymidine