In vitro effect of statins on cytokine production and mitogen response of human peripheral blood mononuclear cells

doi:10.1016/j.clim.2005.06.014

Clinical Immunology

Volume 117, Issue 1, October 2005, Pages 73-77

https://doi.org/10.1016/j.clim.2005.06.014 Get rights and content

Abstract

The in vitro effect of the hydrophilic statin – pravastatin – and three hydrophobic statins – atorvastatin, lovastatin and simvastatin – on the production of IL-1β, IL-1ra, IL-2, IL-6 and IFN-γ by human peripheral blood mononuclear cells (PBMC) and their response to mitogens was examined. Lovastatin and simvastatin increased the production of IL-1β in a dose dependent manner and reduced secretion of IL-1ra at high concentration. These two statins exerted a dose dependent inhibitory effect on IL-2 production and reduced the secretion of IFNγ at high dose. Atorvastatin did not affect IL-1β, but suppressed IL-1ra, IL-2 and IFNγ production. Atorvastatin, lovastatin and simvastatin caused a dose dependent inhibition of mitogen-induced proliferation of PBMC. IL-6 production was not affected by any one of the statins. While pravastatin caused a slight reduction in the proliferative response of PBMC to PHA, it did not affect either their response to Con A and PWM, or the secretion of cytokines tested.

Introduction

The beneficial effect of statins (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors) in reducing the risk of cardiovascular events is nowadays widely recognized. This activity is attributed mainly to their lowering cholesterol capacity, although an anti-atherosclerotic effect has been demonstrated either by their direct action on the arterial wall [1], or by an inhibition of oxidized low density lipoprotein-induced macrophage-derived foam cell growth [2]. Recently, the concept that the immune system exerts a major role in development of atherosclerosis and that atherosclerosis is in fact an inflammatory disease gains broader support [3], [4], [5]. A number of studies have shown that the protective role of statins on the cardiovascular system is due in part to their anti-inflammatory properties. Therefore, modulation of immune responses with drugs and especially with statins may prevent progression of this condition. Ascer et al. [6] have reported on a significant reduction in the levels of proinflammatory cytokines TNFα, IL-1β, IL-6, as well as CRP and soluble intercellular adhesion molecule-1 following atorvastatin administration in hypercholesterolemic patients, compared with individuals subjected to a cholesterol lowering diet alone. Okopien et al. [7] have found that dyslipidemic patients who exhibited higher release of IFN-γ and IL-2 than healthy controls, showed a decrease in those cytokine levels following treatment with fluvastatin or simvastatin. The inhibitory effect of various statins on proinflammatory cytokines has been detected in different types of cells such as human T-lymphocytes [7], bone marrow-derived dendritic cells [8], peripheral blood mononuclear cells (PBMC) [9], glomerular mesengial cells [10] and adipocytes [11].

The purpose of the present study was to compare the in vitro effect of four statins, i.e. the hydrophilic one, pravastatin, and the hydrophobic atorvastatin, lovastatin and simvastatin on the production of IL-1β, IL-1ra, IL-2, IL-6 and IFN-γ by human peripheral blood mononuclear cells (PBMC). In addition, the mitogen response of PBMC following incubation with these statins was examined.

Section snippets

Statins

Atorvastatin, lovastatin, pravastatin and simvastatin were kindly provided by Teva, Pharmaceutical Industries Ltd., API Division, Petah Tiqva, Israel. Atorvastatin calcium was dissolved in dimethyl sulphoxide (DMSO, Sigma, Israel), lovastatin and simvastatin were dissolved in absolute ethanol and pravastatin in phosphate buffered saline (PBS). A stock solution of 5 mM of each statin was prepared in the appropriate diluent, and further dilutions—in medium. The statins were added to the cell

IL-1β

Control PBMC produced 3.6 ± 0.23 ηg/ml IL-1β, whereas cells incubated with 10 μM of lovastatin and simvastatin showed increased IL-1β secretion −5.34 ± 0.35 ηg/ml (48%) and 4.33 ± 0.2 ηg/ml (37%), respectively (P < 0.04). At a concentration of 50 μM, the drugs further enhanced IL-1β secretion −5.8 ± 0.3 ηg/ml (62%) and 6.1 + 0.4 ηg/ml (70%), respectively (P < 0.01). Atorvastatin and pravastatin did not affect IL-1β production (Fig. 1).

IL-1ra

The amount of IL-1ra produced by control cells was 15.8 ±

Discussion

The results of the present study show that under the above described experimental conditions statins modulate the capacity of PBMC to produce cytokines. However, the production of the cytokines tested was not affected likewise by all four statins. Pravastatin at both concentrations did not exert any effect on the cytokine secretion. Incubation with lovastatin and simvastatin increased the secretion of IL-1β and reduced IL-2 production in a dose dependent manner, whereas atorvastatin did not

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Contact lenses for pravastatin delivery to eye segments: Design and in vitro-in vivo correlations
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Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design contact lenses (CLs) that can sustainedly deliver pravastatin and thus improve the ocular efficacy while avoiding systemic side effects of statins. Bioinspired hydrogels were prepared with monomers that resemble hydrophobic (ethylene glycol phenyl ether methacrylate) and amino (2-aminoethyl methacrylamide hydrochloride) functionalities of the active site of HMG-CoA. Best performing CLs loaded >6 mg/g, in vitro fulfilled the release demands for daily wearing, and showed anti-inflammatory activity (lowering TNF-α). High hydrostatic pressure sterilization preserved the stability of both the drug and the hydrogel network. Ex vivo tests revealed the ability of pravastatin to accumulate in cornea and sclera and to penetrate through transscleral route. In vivo tests (rabbits) confirmed that, compared to eye drops and for the same dose, CLs provided significantly higher pravastatin levels in tear fluid within 1 to 7 h of wearing. Moreover, after 8 h wearing pravastatin was present in cornea, sclera, aqueous humour and vitreous humour. Strong correlations between percentages of drug released in vitro and in vivo were found. Effects of volume and proteins on release rate and Levy plots were identified.
Effect of statin use on the risk of medically attended acute respiratory illness among influenza vaccinated elderly
2018, Vaccine
Citation Excerpt :
Different statins were reported to have different inhibitory effects because of the different chemical structures of statins, namely, the hexahydronaphthalene moiety [22,23]. Two stains that contain the hexahydronaphthalene moiety, simvastatin and lovastatin, has been reported to have stronger immunomodulatory effect than other statins that do not contain this chemical structure [22–25]. Further investigation into the mechanism of action of individual statins’ immunomodulatory effects is warranted.
The immunomodulatory effects of statins may reduce the immune response induced by influenza vaccines. However, evidence regarding the effect of statin use on the effectiveness of seasonal influenza vaccines against medically attended acute respiratory illness (MAARI) in the elderly remains scarce.
We conducted a retrospective cohort study using data from Taiwan’s National Health Insurance Research Database. Elderly adults aged ≧ 66 years who were vaccinated with seasonal influenza vaccines during the 2007–2008 to 2012–2013 influenza seasons were enrolled for this analysis. We compared the risk of MAARI between statin and non-statin users. Propensity score matching and conditional logistic regression models were used to analyze the data.
A total of 440,180 elderly were included in this study. In general, the risk of MAARI was higher in statin users than non-statin users (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.02–1.05). Statin exposure after vaccination was associated with a higher risk of MAARI (OR: 1.05, 95% CI: 1.02–1.07). Among different statin agents, simvastatin and lovastatin use was associated with a significant increase in the risk of MAARI (OR_simvastatin: 1.14, 95% CI: 1.10–1.18; OR_lovastatin: 1.18, 95% CI: 1.12–1.25).
Statin exposure, especially simvastatin and lovastatin, was associated with a higher risk of MAARI in the seasonal influenza vaccinated elderly. Future studies exploring the differences between individual statins and mechanisms of their immunomodulatory effects are necessary.
HMG-CoA reductase inhibitors pravastatin, lovastatin and simvastatin suppress delayed rectifier K<sup>+</sup>-channel currents in murine thymocytes
2014, Pharmacological Reports
Citation Excerpt :
Therefore, our results indicated that, compared to pravastatin, lovastatin and simvastatin are more likely to induce membrane depolarization of lymphocytes, which counteracts the Ca2+ influx into the cells, leading to the decreased immune activity. This may explain the higher immunosuppressive potency of lovastatin and simvastatin than pravastatin, as previously demonstrated in in vitro studies [4]. Moreover, as we have recently shown with benidipine [9], the persistent effect of simvastatin on the decreased channel currents may predict its longer duration of action in thymocytes.
Since lymphocytes predominantly express delayed rectifier K⁺-channels (Kv1.3) that trigger lymphocyte activation, statins, which exert immunosuppressive effects, would affect the channel currents.
Employing the patch-clamp technique in murine thymocytes, we examined the effects of statins on Kv1.3-channel currents and the membrane capacitance (C_m).
Pravastatin significantly suppressed the pulse-end currents of the channels. Lovastatin and simvastatin also suppressed the peak currents, significantly decreasing the C_m.
This study demonstrated for the first time that statins inhibit thymocyte Kv1.3-channels. The slow inactivation patterns induced by lovastatin and simvastatin may be associated with their accumulation in the plasma membranes.
Statins directly suppress cytokine production in murine intraepithelial lymphocytes
2013, Cytokine
Statins, inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are known not only as cholesterol-lowering agents but also as anti-inflammatory mediators. However, their regulatory effect on intestinal mucosal immunity remains unclear. The present study examined the possible direct effects of statin on intestinal intraepithelial lymphocytes (IELs), the front line cells of the intestinal mucosal immune system. Murine IELs were isolated from the small intestines of C57BL/6 mice. IELs activated with anti-CD3/CD28 monoclonal antibodies produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-4 in significant numbers; however, they did not produce IL-5. Both simvastatin and lovastatin suppressed IEL production of IFN-γ, TNF-α, IL-2, and IL-4 in a dose-dependent manner, whereas 48-h treatment with high concentrations (5 × 10⁻⁵ M) of simvastatin and lovastatin did not affect the number of IELs. The suppressive effect of the simvastatin was significantly restored by the addition of mevalonate, farnesyl pyrophosphate ammonium salt, and geranylgeranyl pyrophosphate ammonium salt, which are downstream metabolites of HMG-CoA. These findings suggest that statins have direct suppressive effects on the production of T helper 1-cytokines and IL-4 in IELs; these effects are associated with inhibition of the mevalonate pathway to some extent.
Early statin use is associated with increased risk of infection after stroke
2013, Journal of Stroke and Cerebrovascular Diseases
Infection after stroke is common and likely detrimental. Given the potent immunomodulatory properties of statins, we hypothesized that early statin use might increase the risk of infection in the immediate post stroke period.
In a study cohort of 112 patients with ischemic stroke, we assessed the impact of early statin use on the risk of post stroke infection.
After controlling for stroke severity and patient age, the odds ratio (OR) and 95% confidence interval (CI) for infection in the first 15 days after stroke among patients on a statin by day 3 after stroke was 7.21 (95% CI 1.40-37.98; P = .018). When controlling for univariate predictors of infection, the OR associated for infection associated with statin use actually increased, but was no longer significant (8.49 [95% CI 0.92-77.98]; P = .059). In addition, early statin use was associated with an increase in plasma interleukin-1 receptor antagonist (IL-1ra); IL-1ra was significantly higher in early statin users than in nonstatin users by day 7 after stroke.
Our data suggest that early statin use appears to be associated with and increased risk of post stroke infection. This risk may, in part, be related to increases in plasma IL-1ra. If these findings are replicated in larger studies, they could have important implications for the timing of statin therapy after stroke.
Statins as modulators of colon cancer cells induced cytokine secretion by human PBMC
2011, Vascular Pharmacology
Citation Excerpt :
The inhibition of IL-1ra secretion was similar for both types of cells in this experimental model (56% and 54% respectively). It should be noted that simvastatin may exert a dose dependent inhibitory effect on the capacity of PBMC to produce IFNγ, but only after their stimulation with a mitogen as we have shown in a previous study (Bessler et al., 2005). In the present work the dose dependent inhibition of the pro-inflammatory IFNγ produced by PBMC caused by simvastatin proceeded by induction with both type of malignant cells.
The study was designed to examine whether the hydrophilic statin — pravastatin and the hydrophobic statin — simvastatin affect colon cancer cell-induced cytokine secretion by peripheral blood mononuclear cells (PBMC). Statins were added to human colon cancer cells (HT-29 and RKO), or to PBMC incubated separately or jointly. The secretion of the pro-inflammatory cytokines IL-1β and IFNγ and that of the anti-inflammatory cytokines IL-1ra and IL-10 induced by cancer cells was decreased by simvastatin but not by pravastatin, whereas that of IL-6 was not affected by both drugs. Conditioned media from colon cancer cells incubated with either simvastatin or pravastatin induced stimulation of cytokine production by PBMC similar to that caused by conditioned media derived from cancer cells incubated without the drugs, suggesting that simvastatin acts directly on the interaction between cancer and PBM cells. Simvastatin, but not pravastatin, caused inhibition of both cancer cell proliferation. The results imply that simvastatin may affect inflammation-induced colon cancer proliferation via alteration of the equilibrium between pro- and anti-inflammatory cytokines.

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In vitro effect of statins on cytokine production and mitogen response of human peripheral blood mononuclear cells

Abstract

Introduction

Section snippets

Statins

IL-1β

IL-1ra

Discussion

Atherosclerosis

Atherosclerosis

Atherosclerosis

Clin. Chim. Acta

Life Sci.

Atherosclerosis

Trasplant. Immunol.

Biol. Chem.

Immunopharmacology

Pleiotropic events of statins in atherosclerosis and diabetes

Diabetes Care

Immunomodulation for treatment and prevention of atherosclerosis

Autoimmun. Rev.

Mechanisms of action of statins and their pleiotropic effects

Ann. Endocrinol. (Paris)

Inflammatory cytokines and cardiovascular disease

Curr. Drug Targets Inflamm. Allergy