Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro

Kurakata, Shinichi; Kada, Mari; Shimada, Yohko; Komai, Takashi; Nomoto, Kikuo

doi:10.1016/0162-3109(96)00108-7

Cited by 90 publications

(40 citation statements)

References 14 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: 79%

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: 79%

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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“…To this end, human peripheral blood mononuclear cells (PBMC) and human endothelial cells (EC) were treated for 24 hours with increasing concentrations of lipophilic inhibitors of HMG-CoA reductase, lovastatin or simvastatin (0.1-40 M), before the exposure to inflammatory stimuli. Pravastatin, a hydrophilic statin, was not considered for these studies because of its reported lack of activity in vitro on smooth muscle cell migration, proliferation, and apoptosis (Corsini et al, 1995b(Corsini et al, , 1998Guijarro et al, 1998) and for its weaker inhibitory effect on sterol synthesis (Kurakata et al, 1996;van Vliet et al, 1996). As shown in Figure 1A, lovastatin and simvastatin, at 10 and 40 M, significantly reduced MCP-1 production induced in PBMC by 100 ng/ml LPS ( p Յ 0.01, Student's t test) or 0.005 KE/ml inactivated Streptococcus hemoliticus ( p Յ 0.01, Student's t test), whereas doses below 10 M were ineffective.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Monocyte Chemotactic Protein-1 Synthesis by Statins

Romano

Diomede

Sironi

et al. 2000

Laboratory Investigation

279

141

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SUMMARY:The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti-inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1␤. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action. (Lab Invest 2000, 80:1095-1100.

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“…23 Because mevalonate is the precursor not only of cholesterol but also of many other nonsteroidal isoprenoid products, HMG-CoA reductase inhibition might affect several other cellular functions. In this context, suppression of T-cell responses 24 reduced expression of class II major histocompatibility complexes on antigen-presenting cells, 12 and reduced chemokine synthesis in peripheral blood mononuclear cells 25 has been demonstrated. In addition, it was recently reported by Weitz-Schmidt et al 26 that several statins (including simvastatin) are capable of blocking the LFA-1-ICAM-1 interaction, providing a mevalonate and thus HMG-CoA reductase-independent pathway for anti-inflammatory and immunomodulatory statin actions.…”

Section: Discussionmentioning

confidence: 99%

HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis

et al. 2004

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Background-HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. Methods and Results-Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24Ϯ0.09 to 0.87Ϯ0.11 mL · min Ϫ1 · g Ϫ1 in untreated mice (PϽ0.005; nϭ12), while remaining unaltered (1.21Ϯ0.08 mL · min Ϫ1 · g Ϫ1 at baseline and 1.15Ϯ0.1 mL · min Ϫ1 · g

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Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro

Cited by 90 publications

References 14 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

Inhibition of Monocyte Chemotactic Protein-1 Synthesis by Statins

HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis

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