Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

Hillyard, Dianne; Nutt, Cian D.; Thomson, J. G.; McDonald, Kenneth J; Wan, Rui; Cameron, Angus J.M.; Mark, Patrick B.; Jardine, Alan G.

doi:10.1016/j.atherosclerosis.2006.05.037

Cited by 37 publications

(31 citation statements)

References 30 publications

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“…In line with these findings we did not detect any reduction in intracellular cholesterol levels of NK cells treated with statins. These data are in contrast to a recently published study [16], which demonstrated that statin treatment could interfere with lipid rafts in NK cells. To reconcile these differences we analyzed membrane rafts by isolating detergent resistant membrane fractions (DRMs) from the human NK-cell line NKL.…”

Section: Discussioncontrasting

confidence: 99%

“…We did not observe any depletion of typical raft markers such as the Srcfamily kinase Fyn from DRMs upon treatment of NKL cells with 1 mM simvastatin (data not shown), again arguing against a role of membrane raft depletion in the simvastatin-mediated NK-cell inhibition. However, at higher concentrations of simvastatin (up to 5 mM) we observed a strong depletion of Fyn from DRMs (data not shown), consistent with the results of Hillyard et al [16]. This demonstrates that while simvastatin can have a depleting effect on membrane rafts, this effect is only obvious at higher concentrations of the drug while it is not detectable at lower concentrations, which are still effective in blocking NK-cell cytotoxicity.…”

supporting

confidence: 91%

“…However, at higher concentrations of simvastatin (up to 5 mM) we observed a strong depletion of Fyn from DRMs (data not shown), consistent with the results of Hillyard et al [16]. This demonstrates that while simvastatin can have a depleting effect on membrane rafts, this effect is only obvious at higher concentrations of the drug while it is not detectable at lower concentrations, which are still effective in blocking NK-cell cytotoxicity.The statin concentrations used in this study (5 mM for primary human NK cells) are similar to the ones used by other researchers for their ex vivo studies [15,16]. However, they are about one order of magnitude higher that the levels reached in many patients.…”

supporting

confidence: 91%

“…Also, the function of NK cells can be inhibited by statins. One group reported that in vitro only lipophilic statins could inhibit NK-cell degranulation and cytotoxicity [15].Another group correlated the effects of statins on NK-cell cytotoxicity with a depletion of membrane rafts [16]. As membrane rafts are important for NK-cell function [17], such an effect might explain the statin-mediated inhibition of NK-cell cytotoxicity.…”

mentioning

confidence: 99%

“…These membrane microdomains are enriched in cholesterol and sphingolipids and during NK-cell activation different receptors are recruited to these domains [17,18]. One report suggested that statins inhibit NK-cell cytotoxicity by interfering with membrane rafts through the depletion of cellular cholesterol [16]. To test if statin treatment affects lipid rafts in NK cells, we stained cells with FITClabeled cholera toxin b subunits (FITC-CTx).…”

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confidence: 99%

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

2009

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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...

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Section: Discussioncontrasting

confidence: 99%

supporting

confidence: 91%

supporting

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

2009

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Medical Therapies: Statins

Sokalska¹,

Dulęba²

2011

Endometriosis

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Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

Shao,

Bai,

Zhu

et al. 2023

Adv Healthcare Materials

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Natural killer (NK) cells have emerged as an important contributor to cancer immunotherapy, but their antitumor efficacy remains suboptimal. While cytokine‐based priming shows promise in enhancing NK‐cell activity, its clinical translation faces many challenges, including co‐activation of multiple cytokines, poor pharmacokinetics, and limited mechanistic understanding. Here, we developed a polymeric micelle‐based IL‐15/IL‐2 codelivery system (IL‐15/2‐PEG‐PTMC) for NK‐cell activation. In vivo studies demonstrated that the half‐life of IL‐15 and IL‐2 as well as the recruitment of NK cell within tumor tissue was significantly increased after PEG‐PTMC loading. Coupled with the coactivation effect of IL‐15 and IL‐2 conferred by this polymeric micelle‐based system, it noticeably delayed the growth of tumors in mice compared to conventional NK cell activation approach, that was free IL‐15 and IL‐2. We also surprisingly found that cholesterol metabolism was highly involved in the NK cell activation by IL‐15/2‐PEG‐PTMC. Following stimulation with IL‐15/2‐PEG‐PTMC or IL‐15, NK cells underwent a series of cholesterol metabolism reprogramming, which elevated the cholesterol levels on the NK cell membrane. This in turn promoted the formation of lipid rafts and actived immune synapse, effectively contributing to the enhancement of the NK cell's anti‐tumor activity. We believe this will open a new avenue for improving the efficacy of NK cell immunotherapy by regulating cholesterol metabolism.This article is protected by copyright. All rights reserved

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Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

Cited by 37 publications

References 30 publications

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

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

Medical Therapies: Statins

Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

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