ABSTRACT
Statins are potent lipid-lowering drugs but anti-inflammatory effects have also been suggested. Our aim was to investigate the effects of simvastatin on proinflammatory cytokines and matrix metalloproteinases (MMPs). Eighty hypercholesterolemic men were randomized to simvastatin 40 mg or placebo for 6 weeks. Simvastatin treatment significantly reduced C-reactive protein (CRP) levels while interleukin (IL)-6 levels remained unchanged. The ex vivo release of IL-1ß and IL-6 was not altered by simvastatin, whereas the release of TNF-α and IL-8 increased after 6 weeks of simvastatin treatment. Similarly, the circulating levels of MMP-3 and TIMP-1 remained unaffected by simvastatin while MMP-9 increased. However, none of the effects except for the CRP reduction within the simvastatin group reached statistical significance when compared to the placebo group. Our findings are in contrast to previous in vitro and animal data and question the in vivo relevance of some of the pleiotropic effects of simvastatin.
Subject(s)
C-Reactive Protein/biosynthesis , Cytokines/blood , Hypercholesterolemia/drug therapy , Matrix Metalloproteinases/blood , Simvastatin/pharmacology , Adult , Anticholesteremic Agents/pharmacology , Cholesterol/blood , Humans , Interleukin-1beta/biosynthesis , Interleukin-1beta/blood , Interleukin-6/biosynthesis , Interleukin-6/blood , Interleukin-8/biosynthesis , Interleukin-8/blood , Male , Middle Aged , Simvastatin/administration & dosage , Simvastatin/therapeutic use , Tissue Inhibitor of Metalloproteinase-1/blood , Triglycerides/blood , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/bloodABSTRACT
Statins exert a number of anti-inflammatory and immunomodulatory effects in vitro. However, the immunomodulatory effects in vivo are less clarified. In the present study, we investigated whether simvastatin treatment changed the levels of autoantibodies against specific oxidized LDL (oxLDL) antigens as well as their association with leukocyte activation markers. Eighty volunteers with mild-to-moderate hypercholesterolemia were randomized to either simvastatin 40 mg or placebo for 6 weeks. Autoantibodies against apo B peptide antigens, C-reactive protein (CRP) and interleukin (IL)-6 in plasma were determined by ELISA. Subsets of circulating B and T cells were studied by flow cytometry. Simvastatin significantly reduced CRP by 26%, whereas IL-6 remained unchanged. Levels of IgG against the apo B peptide P-240 (amino acids 3586-3605) increased by 16% (p = 0.03) in the simvastatin group whereas autoantibody levels to other apo B peptides did not change. At baseline and after 6 weeks, the P-240 IgG levels were significantly correlated with the number of CD57+CD28 - CD8+T cells but not to other lymphocyte subsets or inflammatory markers. The P-240 IgG levels after 6 weeks simvastatin therapy was strongly correlated to the relative increase in CD57+CD28 - CD8+T cells (p = 0.003). Simvastatin treatment induced an increase in autoantibodies against an oxLDL antigen. The effect was related to an expansion of a CD8+T cell subset and may involve an immunostimulation by simvastatin.
Subject(s)
Antibody Formation/drug effects , Autoantibodies/blood , CD8-Positive T-Lymphocytes/immunology , Lipoproteins, LDL/immunology , Lymphocyte Activation/immunology , Simvastatin/pharmacology , Apolipoprotein B-100/immunology , Apolipoproteins/blood , Autoantibodies/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , C-Reactive Protein/metabolism , CD8-Positive T-Lymphocytes/cytology , Cell Count , Cholesterol/blood , Cholesterol, LDL/blood , Double-Blind Method , Humans , Immunity, Cellular , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Immunophenotyping , Interleukin-6/blood , Male , Middle Aged , Peptide Fragments/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , Treatment OutcomeABSTRACT
OBJECTIVE: The use of statins has shown several anti-inflammatory actions, including modulatory effects on T cells in vitro. Since the effects on human T cells in vivo are less clarified, our aim was to investigate the effects of simvastatin on human T cells in vivo and ex vivo. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. The serum levels of C-reactive protein (CRP) were significantly reduced by simvastatin. The proportions of CD4+ and CD8+ T cell subsets expressing early (CD25) or late (HLA-DR) activation markers, as assessed by flow cytometry, were not changed by simvastatin. However, simvastatin tended to increase the density of HLA-DR and L-selectin per CD8+ T cell. The T helper(h)1/Th2 response was evaluated by stimulatory assays followed by intra-cellular staining of interferon-gamma and interleukin-4. Simvastatin treatment did not affect the Th1 response but the results indicated a potential to suppress Th2. CONCLUSION: Simvastatin treatment resulted in a few discrete changes as regards peripheral T cells. However, the findings do not provide evidence that simvastatin-induced anti-inflammatory actions are related to any significant modulatory effects on human T cells in clinically healthy men with hypercholesterolemia.
