HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis.
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 (1-10microM) for different periods (1-48h), and were subsequently stimulated with a cytokine cocktail (1.25ng/ml TNF-alpha, 1ng/ml Il-1beta, and 0.5microg/ml prostaglandin E(2)) 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.
Yilmaz
Atilla
A
Medical Clinic II, University Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany. a.yilmaz@web.de
Reiss
Christine
C
Tantawi
Omeima
O
Weng
Alexander
A
Stumpf
Christian
C
Raaz
Dorette
D
Ludwig
Josef
J
Berger
Thomas
T
Steinkasserer
Alexander
A
Daniel
Werner G
WG
Garlichs
Christoph D
CD
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D001161:Arteriosclerosis / Q000276:immunology*; D000069059:Atorvastatin; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000032:analysis; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007136:Immunoglobulins / Q000032:analysis; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000032:analysis; D011758:Pyrroles / Q000494:pharmacology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000032:analysis; D019821:Simvastatin / Q000494:pharmacology; D013997:Time Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology; D000097802:CD83 Antigen
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000069059:Atorvastatin; D051940:B7-2 Antigen; D006684:HLA-DR Antigens; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D011758:Pyrroles; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D019821:Simvastatin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000097802:CD83 Antigen; C515370:CCR7 protein, human; C497964:CD86 protein, human