Simvastatin inhibits lymphocyte function in normal subjects and patients with cardiovascular disease

Hillyard, Dianne; Cameron, Angus J.M.; McDonald, Kenneth J; Thomson, J. G.; MacIntyre, Alan; Shiels, Paul G.; Panarelli, Maurizio; Jardine, Alan G.

doi:10.1016/j.atherosclerosis.2004.03.018

Cited by 56 publications

(43 citation statements)

References 32 publications

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“…We, and others, have proposed that some of these effects could be attributed to a reduction in membrane cholesterol (42,43). Moreover, a recent report demonstrates that reducing the cholesterol content of lipid rafts using simvastatin, another HMG-CoA reductase inhibitor, alters downstream signaling in prostate cancer cells (44).…”

Section: Discussionmentioning

confidence: 99%

“…Previous data showing that atorvastatin treatment affects TCR signaling by modulating lipid biosynthesis, resulting in the redistribution of membrane proteins, (Ref. 19 and data not shown) encouraged us to investigate whether this drug could affect the expression and activation of signaling molecules in SLE T cells.…”

Section: Atorvastatin Treatment Restored Total Lck Expression To Normmentioning

confidence: 99%

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Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Jury

Isenberg

Mauri

et al. 2006

The Journal of Immunology

120

104

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Loss of tolerance to self-Ags in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease, is associated with dysregulation of T cell signaling, including the depletion of total levels of lymphocyte-specific protein kinase (Lck) from sphingolipid-cholesterol-enriched membrane microdomains (lipid rafts). Inhibitors of 3-hyroxy-3-methylgluteryl CoA reductase (statins) can modify the composition of lipid rafts, resulting in alteration of T cell signaling. In this study, we show that atorvastatin targets the distribution of signaling molecules in T cells from SLE patients, by disrupting the colocalization of total Lck and CD45 within lipid rafts, leading to a reduction in the active form of Lck. Upon T cell activation using anti-CD3/anti-CD28 in vitro, the rapid recruitment of total Lck to the immunological synapse was inhibited by atorvastatin, whereas ERK phosphorylation, which is decreased in SLE T cells, was reconstituted. Furthermore, atorvastatin reduced the production of IL-10 and IL-6 by T cells, implicated in the pathogenesis of SLE. Thus, atorvastatin reversed many of the signaling defects characteristic of SLE T cells. These findings demonstrate the potential for atorvastatin to target lipid raft–associated signaling abnormalities in autoreactive T cells and provide a rationale for its use in therapy of autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Section: Atorvastatin Treatment Restored Total Lck Expression To Normmentioning

confidence: 99%

Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Jury

Isenberg

Mauri

et al. 2006

The Journal of Immunology

120

104

View full text Add to dashboard Cite

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“…Statinmediated inhibition of cholesterol biosynthesis results in the disruption of lipid rafts [43,44].…”

Section: Discussionmentioning

confidence: 99%

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

Kojro

Füger

Prinzen

et al. 2010

JAD

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Abstract. Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-β protein precursor (AβPP) and are reported to stimulate the activity of α-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the α-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in α-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates α-secretase activity. Treatment of human neuroblastoma cells with 50 µM zaragozic acid resulted in a ∼3 fold increase of α-secretase activity and reduced cellular cholesterol by ∼30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 µM). Zaragozic acid-stimulated secretion of α-secretase cleaved soluble AβPP was dose dependent and saturable. Lovastatin-or zaragozic acid-stimulated increase of α-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the α-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AβPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for α-secretase activation.

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“…1A). Also, another study has demonstrated an inhibitory effect on the function of lymphocytes in patients treated with therapeutic doses of simvastatin [28]. This opens up the possibility to inhibit NK-cell cytotoxicity by statin treatment in a clinical setting.…”

mentioning

confidence: 93%

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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Simvastatin inhibits lymphocyte function in normal subjects and patients with cardiovascular disease

Cited by 56 publications

References 32 publications

Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

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

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