Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis

Tanaka, Toru; Porter, Cynthia M.; Horvath‐Arcidiacono, Judith A.; Bloom, Eda T.

doi:10.1093/intimm/dxl133

Cited by 29 publications

(32 citation statements)

References 59 publications

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“…2E). These results are in line with observations made by others with regard to the differential effects of lipophilic and hydrophilic statins on immune cell function (27,28). One possible explanation for the inability of pravastatin to inhibit B cell activation could be a lack of expression of solute carrier organic anion transporter family member 1B1 (SLCO1B1), which encodes a transporter protein responsible for the cellular uptake of statins.…”

Section: Resultssupporting

confidence: 91%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

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Section: Resultssupporting

confidence: 91%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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“…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.…”

mentioning

confidence: 60%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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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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“…91,92 Briefly, however, these effects include: the induction of apoptosis in CD4 þ T cells; 93 downregulation of chemokine secretion and receptor expression; 94,95 suppressed expression of numerous adhesion molecules on organ tissue and circulating cells; 90,96,97 alteration of cytokine and metalloproteinase expression; 98 modulation of natural killer cell cytotoxic activity. 99,100 More study is required to fully understand how the immunomodulatory effects of statins ultimately impact human cancers.…”

Section: Mid 1970smentioning

confidence: 99%

Targeting tumor cell metabolism with statins

2012

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The mevalonate pathway is a core biochemical process, crucial for the generation of cholesterol and other key metabolic end products. The rate-limiting enzyme of the mevalonate pathway, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is safely and effectively targeted by the statin family of inhibitors to treat hypercholesterolemia. The anticancer activity of statins has also been widely reported, yet the tumor-selective mechanisms that mediate these antiproliferative effects remain largely unclear. The importance of altered metabolism in the context of tumorigenesis has received renewed attention as metabolic changes entwined with the molecular hallmarks of cancer have been elucidated. Although several metabolic pathways have been linked to cancer progression and etiology, it was only recently that HMGCR and the mevalonate pathway were also shown to have a distinct role in cellular transformation. In this review, we chart the historical progression of statins from cholesterol-lowering blockbusters to anticancer agents with imminent potential, and further discuss an emerging role for HMGCR and the mevalonate pathway in the metabolic reprogramming of cancer.

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Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis

Cited by 29 publications

References 59 publications

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

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

Targeting tumor cell metabolism with statins

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