Statins inhibit NK‐cell cytotoxicity by interfering with LFA‐1‐mediated conjugate formation

Abstract

Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, commonly referred to as statins, are inhibitors of cholesterol biosynthesis. They are broadly used for treating hypercholesterolemia and for prevention of cardio-and cerebrovascular diseases. Recent publications show that statins also act as immunomodulatory drugs. Here, we show that lipophilic statins inhibit NK-cell degranulation and cytotoxicity. This effect was reversible by addition of substrates of isoprenylation, but not by addition of cholesterol. In NK-target cell conjugates intracellular Ca 21 flux was unaffected by statin treatment. However, statins strongly reduced the amount of conjugate formation between NK and target cells. This inhibition was paralleled by a statin-dependent inhibition of LFA-1-mediated adhesion and a reduction of NK-cell polarization. This demonstrates that statins impair the formation of effector-target cell conjugates resulting in the disruption of early signaling and the loss of NK-cell cytotoxicity.Key words: Adhesion molecules . Cytotoxicity . Human . NK cells IntroductionNK cells belong to the innate arm of the immune system and are important for an early immune response against viral infections and against tumor formation [1]. They are able to detect and selectively kill potentially dangerous cells. Furthermore, they can secrete cytokines and thereby mediate the communication between the innate and adaptive parts of an immune response. Specific killing of infected and transformed cells depends on several discrete steps that lead to polarization and exocytosis of lytic granules towards the target cell [2,3]. As a very first step the contact between NK cells and potential targets is established. Different NK-cell receptors and adhesion molecules mediate this event. LFA-1 plays a special role in the complete process of NK-cell activation. Engagement of LFA-1 by its ligand ICAM-1 on target cells is the central step in the stable adhesion of NK cells to their target cells and is sufficient to induce the polarization of lytic granules in resting NK cells [4,5]. NK-cell cytotoxicity is achieved by degranulation of these accumulated granules in the direction of the target. For this, mobilization of Ca 21 from intracellular stores is needed, which is mediated by the activation of the phospholipase C-g (PLCg) and PKC signaling pathways [6]. Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, commonly referred to as statins, are potent inhibitors of cholesterol biosynthesis. They mimic HMGCoA and thereby block the active site of this essential enzyme [7]. Statins are broadly used as a pharmacologic therapy for treating hypercholesterolemia and for prevention of cardio-and cerebrovascular diseases [8]. Accumulating evidence occurs that statins also act as immunomodulatory drugs [9][10][11]. In various experimental settings they were shown to affect different kinds of immune cells including T cells [12,13], B cells [14] and antigenpresenting cells [13]. Also, the function of NK cells can be inh...

Statin use and the risk of kidney cancer: a population-based case–control study

“…Statins have been shown to increase regulatory T-cell numbers and functionality in vivo [45,46]; both lipophilic and hydrophilic statins decrease natural killer cell cytotoxicity [47,48]. These immunosuppressive effects of statins might impair host antitumor immune responses.…”

IL-2 Costimulation Enables Statin-Mediated Activation of Human NK Cells, Preferentially through a Mechanism Involving CD56+ Dendritic Cells

“…The effects of statins on NK cells reported so far were all inhibitory (9)(10)(11)(12). In all these studies, which focused on NK celltarget cell interactions, purified NK cells were used in coculture with target cells but the role of APCs had not been investigated at all.…”

“…Although it is well established that statins are predominantly anti-inflammatory and immunosuppressive agents, an increasing number of studies have shown that statins may also induce proinflammatory responses depending on costimulatory signals (5)(6)(7)(8). In contrast, with regard to NK cells, only inhibitory effects have been reported so far (9)(10)(11)(12). However, all these studies focused on NK cell-target cell interactions but did not investigate the role of antigen-presenting cells (APC) in statin-mediated NK cell modulation.…”

Statin use and risk of kidney cancer: a meta-analysis of observational studies and randomized trials

“…Further, statins have been shown to increase regulatory T-cell numbers and functionality in vivo [41][42][43]. Both lipophilic and hydrophilic statins decrease natural killer cell cytotoxicity [44]. These immunosuppressive effects of statins might impair host antitumour immune responses, suggesting an opposing effect on tumour development, which should be considered.…”