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

Abstract

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.

Immunomodulatory Effects of Statins

“…These include effects on the intimal recruitment, differentiation, proliferation, and secretory activity of a number of immune cells, mainly monocyte/macrophages and T cells (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Although many of these effects may be caused by-or be synergistic with-similar effects of lower cholesterol levels in plasma or atherosclerotic lesion, two previously unknown immune effects of statins of potential clinical relevance have been recently reported (23,24).…”

Tolerance and chronic rejection

“…In one of the studies, cytotoxicity of natural killer (NK) cells was found to be lower in patients treated with the HMG-CoA reductase inhibitors compared with controls (Kobashigawa et al 1995). In fact, in vitro studies have shown inhibition of NK cell activity by HMG-CoA reductase inhibitors that can be reversed by treatment with interleukin 2 (IL-2) (Cutts & Bankhurst 1990;Cutts et al 1989). It is also possible that lowering plasma lipids enhanced the uptake of the lipophilic drug, CsA, resulting in enhanced immunosuppression.…”

Survival, Graft Atherosclerosis, and Rejection Incidence in Heart Transplant Recipients Treated With Statins: 5-Year Follow-up

“…2 Similarly, lovastatin has been shown to potentiate the effects of cyclosporine, resulting in altered synthesis of interleukin-2. 5 Some investigators have maintained that statins exert their immunosuppressive effects by increasing the bioavailability of cyclosporine, 7,8 whereas others maintain that this is not so. 9 Results of clinical trials have confirmed the immunosuppressive effects of statins at the molecular level.…”

“…They also appeared to exert immunosuppressive and immunomodulatory effects, including the inhibition of monocyte chemotaxis 1 and the reduction of natural killer cell and humoral toxicity. [2][3][4][5] Katznelson et al demonstrated that pravastatin acts synergistically with cyclosporine to inhibit vascular smooth muscle mitogenesis 6 and to reduce cytotoxic T-lymphocyte activity. 2 Similarly, lovastatin has been shown to potentiate the effects of cyclosporine, resulting in altered synthesis of interleukin-2.…”