HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis
Introduction
In atherosclerosis, the immune response to various autoantigens such as oxidized low density lipoprotein (oxLDL), heat shock protein 65/60, and β2-glycoprotein Ib sustains inflammatory mechanisms, leading to the progression and destabilization of atherosclerotic plaques [1]. Therefore, cells of the innate and adaptive immunity play a central role in atherosclerosis.
Dendritic cells (DC) are “professional” antigen-presenting cells with the unique ability to initiate a primary immune response to certain antigens by the activation of “naı̈ve” T cells [2]. The importance of DC in different diseases, including tumors, viral and bacterial infections, autoimmune diseases, and transplant rejection, is well known [3]. The maturation of DC with the upregulation of costimulatory molecules (e.g. CD83, CD40, CD86) and MHC class molecules (e.g. HLA-DR) is required to enable DC to activate T cells [2].
Recently, DC were detected in atherosclerotic plaques of vascular specimens [4], [5]. The colocalization of DC and T cells, as well as the expression of HLA-DR and costimulatory molecules on DC in atherosclerotic plaques, suggest that DC initiate an antigen-specific immune response, contributing to the progression of atherosclerosis [6]. Corresponding to this hypothesis, recent investigations have shown that DC maturation was induced by different atherogenic stimuli such as oxLDL, lysophosphatidylcholine, nicotine, angiotensin II, and atrial natriuretic peptide, enabling these mature DC to induce an antigen-specific T cell activation [7], [8], [9], [10], [11]. In addition, it was recently shown that the recruitment of DC into the vascular wall is increased by atherogenic stimuli such as oxLDL, TNF-α, and hypoxia [12].
Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, inhibit the biosynthesis of mevalonate. Mevalonate is a precursor of cholesterol, as well as isoprenoid intermediates such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) [13]. Statin therapy was shown to effectively reduce ischemic events in patients with cardiovascular diseases [14]. Subgroup analyses of large clinical trials suggested that statins possess, beyond their cholesterol lowering function, additional anti-atherosclerotic effects, which have been partly elucidated in recent years [15]. These effects are mainly mediated through the decrease of the isoprenoid intermediates FPP and GGPP. Systemic inflammation in atherosclerosis is suppressed by statins as shown by the reduction of certain inflammatory markers such as CRP during statin treatment [16]. In addition, atherosclerotic plaques are stabilized by statins through the increase of collagen content and the decrease of lipid content, macrophage accumulation and matrix metalloproteinases release [17]. Moreover, in recent publications it was shown that statins are able to modulate immune responses by the suppression of MHC II on interferon γ-stimulated, “non-professional” antigen-presenting cells, such as human endothelial cells or macrophages [18], [19].
The aim of the present study was to analyze the effect of statins on the function of human myeloid DC. For this purpose, we incubated DC with different concentrations of simvastatin or atorvastatin before cytokine stimulation, and subsequently analyzed their morphology, their expression of maturation markers, and their antigen-presenting function.
Section snippets
Cell culture medium and reagents
Cells were cultured in RPMI 1640 (BioWhittaker, Walkersville, MD) supplemented with 300 μg/ml glutamine (BioWhittaker), 100 U/ml penicillin/streptomycin, 10 mM Hepes (Sigma, St. Louis, MO), and 1% heat-inactivated human serum from a healthy donor (blood group AB). Simvastatin and atorvastatin were kindly provided by Merck (Darmstadt, Germany) and Pfizer (Karlsruhe, Germany), respectively. Mevalonate, FPP, and GGPP were obtained from Sigma.
Generation of DC
Monocyte-derived DC were generated according to a
DC morphology
In our study, the effects of different statins (simvastatin and atorvastatin) on the maturation process of DC were investigated. Immature DC, which were neither statin-treated nor cytokine-stimulated (s−/c−-DC), exhibited certain morphological features such as elongated shape, a smooth cell surface, and a great adherence to the culture dishes (Fig. 1A). After maturation induced by cytokine stimulation without statin treatment (s−/c+-DC), DC showed a round shape, “needle-like” cell processes
Discussion
In the present study, we describe for the first time an inhibitory effect of statins on the maturation and antigen-presenting function of human myeloid DC. Preincubation of DC with 10 μM simvastatin or atorvastatin for 48 h caused a complete suppression of cytokine-induced maturation. Thus, the upregulation of maturation markers with defined functions on DC such as CD83, CD40, CD86 (T cell costimulation), HLA-DR (MHC class II for antigen-presentation), and CCR7 (chemokine receptor for DC
Acknowledgements
This work was supported by the Federal Ministry of Education and Research (BMBF) and the Interdisciplinary Center for Clinical Research (IZKF) of the University Erlangen–Nuremberg. We are grateful to Dr. Iwona Cicha and Prof. Dr. Margarete Goppelt-Strübe for their helpful comments and corrections of the present work.
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