Advertisement

HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis

      Abstract

      The beneficial effects of statins in atherosclerosis have been partly attributed to their immunomodulating functions. Dendritic cells (DC), which are “professional” antigen-presenting cells, were recently detected in atherosclerotic plaques. It is assumed that DC play a critical role in the immunological processes related to atherosclerosis. Thus, we investigated the effects of statins on maturation and antigen-presenting function of DC. Human monocyte-derived DC were incubated with simvastatin or atorvastatin (1–10 μM) for different periods (1–48 h), and were subsequently stimulated with a cytokine cocktail (1.25 ng/ml TNF-α, 1 ng/ml Il-1β, and 0.5 μg/ml prostaglandin E2) to induce maturation. In contrast to untreated DC, statin-preincubated DC exhibited an immature phenotype and a significantly lower expression of the maturation-associated markers CD83, CD40, CD86, HLA-DR, and CCR7. The inhibitory statin effect was completely reversed by mevalonate or geranylgeranyl pyrophosphate. In addition, preincubation with statins significantly reduced the ability of cytokine-stimulated DC to induce T cell proliferation. In the present study, we have shown that statins inhibit the maturation and antigen-presenting function of human myeloid dendritic cells, thus maybe contributing to their beneficial effects in atherosclerosis. Therefore, the use of statins as immunomodulators might also provide a new therapeutic approach to other immunological disorders.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hansson G.K.
        • Libby P.
        • Schonbeck U.
        • Yan Z.Q.
        Innate and adaptive immunity in the pathogenesis of atherosclerosis.
        Circ. Res. 2002; 91: 281-291
        • Banchereau J.
        • Briere F.
        • Caux C.
        • Davoust J.
        • Lebecque S.
        • Liu Y.J.
        • et al.
        Immunobiology of dendritic cells.
        Annu. Rev. Immunol. 2000; 18: 767-811
        • Hart D.N.
        Dendritic cells: unique leukocyte populations which control the primary immune response.
        Blood. 1997; 90: 3245-3287
        • Bobryshev Y.V.
        • Lord R.S.
        Ultrastructural recognition of cells with dendritic cell morphology in human aortic intima. Contacting interactions of Vascular Dendritic Cells in athero-resistant and athero-prone areas of the normal aorta.
        Arch. Histol. Cytol. 1995; 58: 307-322
        • Bobryshev Y.V.
        • Lord R.S.
        S-100 positive cells in human arterial intima and in atherosclerotic lesions.
        Cardiovasc. Res. 1995; 29: 689-696
        • Bobryshev Y.V.
        • Lord R.S.
        Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions.
        Cardiovasc. Res. 1998; 37: 799-810
        • Alderman C.J.
        • Bunyard P.R.
        • Chain B.M.
        • Foreman J.C.
        • Leake D.S.
        • Katz D.R.
        Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro- environment?.
        Cardiovasc. Res. 2002; 55: 806-819
        • Coutant F.
        • Perrin-Cocon L.
        • Agaugue S.
        • Delair T.
        • Andre P.
        • Lotteau V.
        Mature dendritic cell generation promoted by lysophosphatidylcholine.
        J. Immunol. 2002; 169: 1688-1695
        • Aicher A.
        • Heeschen C.
        • Mohaupt M.
        • Cooke J.P.
        • Zeiher A.M.
        • Dimmeler S.
        Nicotine strongly activates dendritic cell-mediated adaptive immunity: potential role for progression of atherosclerotic lesions.
        Circulation. 2003; 107: 604-611
        • Nahmod K.A.
        • Vermeulen M.E.
        • Raiden S.
        • Salamone G.
        • Gamberale R.
        • Fernandez-Calotti P.
        • et al.
        Control of dendritic cell differentiation by angiotensin II.
        FASEB J. 2003; 17: 491-493
        • Morita R.
        • Ukyo N.
        • Furuya M.
        • Uchiyama T.
        • Hori T.
        Atrial natriuretic peptide polarizes human dendritic cells toward a th2-promoting phenotype through its receptor guanylyl cyclase-coupled receptor a.
        J. Immunol. 2003; 170: 5869-5875
        • Weis M.
        • Schlichting C.L.
        • Engleman E.G.
        • Cooke J.P.
        Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1817-1823
        • Goldstein J.L.
        • Brown M.S.
        Regulation of the mevalonate pathway.
        Nature. 1990; 343: 425-430
        • Koh K.K.
        Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability.
        Cardiovasc. Res. 2000; 47: 648-657
        • Takemoto M.
        • Liao J.K.
        Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.
        Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1712-1719
        • Jialal I.
        • Stein D.
        • Balis D.
        • Grundy S.M.
        • Adams-Huet B.
        • Devaraj S.
        Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels.
        Circulation. 2001; 103: 1933-1935
        • Crisby M.
        • Nordin-Fredriksson G.
        • Shah P.K.
        • Yano J.
        • Zhu J.
        • Nilsson J.
        Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization.
        Circulation. 2001; 103: 926-933
        • Kwak B.
        • Mulhaupt F.
        • Myit S.
        • Mach F.
        Statins as a newly recognized type of immunomodulator.
        Nat. Med. 2000; 6: 1399-1402
        • Mach F.
        Immunosuppressive effects of statins.
        Atheroscler. Suppl. 2002; 3: 17-20
        • Romani N.
        • Reider D.
        • Heuer M.
        • Ebner S.
        • Kampgen E.
        • Eibl B.
        • et al.
        Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability.
        J. Immunol. Methods. 1996; 196: 137-151
        • Jonuleit H.
        • Kuhn U.
        • Muller G.
        • Steinbrink K.
        • Paragnik L.
        • Schmitt E.
        • et al.
        Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions.
        Eur. J. Immunol. 1997; 27: 3135-3142
        • Lyons A.B.
        • Parish C.R.
        Determination of lymphocyte division by flow cytometry.
        J. Immunol. Methods. 1994; 171: 131-137
        • Lutz M.B.
        • Schuler G.
        Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?.
        Trends Immunol. 2002; 23: 445-449
        • Essig M.
        • Nguyen G.
        • Prie D.
        • Escoubet B.
        • Sraer J.D.
        • Friedlander G.
        3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins.
        Circ. Res. 1998; 83: 683-690
        • Hernandez-Perera O.
        • Perez-Sala D.
        • Soria E.
        • Lamas S.
        Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells.
        Circ. Res. 2000; 87: 616-622
        • Laufs U.
        • Marra D.
        • Node K.
        • Liao J.K.
        3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(kip1).
        J. Biol. Chem. 1999; 274: 21926-21931
        • Kobayashi M.
        • Azuma E.
        • Ido M.
        • Hirayama M.
        • Jiang Q.
        • Iwamoto S.
        • et al.
        A pivotal role of Rho GTPase in the regulation of morphology and function of dendritic cells.
        J. Immunol. 2001; 167: 3585-3591
        • Phipps R.P.
        Atherosclerosis: the emerging role of inflammation and the CD40–CD40 ligand system.
        Proc. Natl. Acad. Sci. USA. 2000; 97: 6930-6932
        • Wagner A.H.
        • Gebauer M.
        • Guldenzoph B.
        • Hecker M.
        3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1784-1789
        • Kobashigawa J.A.
        • Katznelson S.
        • Laks H.
        • Johnson J.A.
        • Yeatman L.
        • Wang X.M.
        • et al.
        Effect of pravastatin on outcomes after cardiac transplantation.
        N. Engl. J. Med. 1995; 333: 621-627