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Atorvastatin Inhibits T Cell Activation through 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase without Decreasing Cholesterol Synthesis¹

Norbert Blank^2,*, Martin Schiller^*, Stefan Krienke^*, Freja Busse^*, Birgit Schätz, Anthony D. Ho^*, Joachim R. Kalden and Hanns-Martin Lorenz^*

^* Department of Medicine V, Division of Rheumatology, University of Heidelberg, Heidelberg, Germany; and Department of Medicine III and Institute of Clinical Immunology and Rheumatology, University of Erlangen-Nuremberg, Erlangen, Germany

The localization of the TCR and other signaling molecules in membrane rafts (MR) is essential for the activation of T lymphocytes. MR are stabilized by sphingolipids and cholesterol. Activation of T lymphocytes leads to the confluence of small MR and the formation of an immunological synapse that is essential for sustained activation and proliferation. In this study, we investigated the effect of statins on MR and T cell activation in superantigen-stimulated human PBMC. Atorvastatin significantly inhibited cellular activation and proliferation. The binding of cholera toxin B subunit to isolated MR and to whole cells was inhibited by low doses of statins. Statins reduce the association of critical signaling proteins such as Lck and linker of activation in T cells with MR in stimulated T cells. The expression of activation markers CD69 and CD25 was inhibited. Several statin-mediated mechanisms, such as a lower stimulation with MHC-II, an inhibition of costimulation by direct binding of statins to LFA-1, a reduced secretion of cytokines, or a depletion of cellular cholesterol pools, were excluded. Inhibition of protein prenylation had a similar effect on T cell proliferation, suggesting that a reduced protein prenylation might contribute to the statin-mediated inhibition of T cell activation. Statins induce both lower levels of low-density lipoprotein cholesterol and inhibition of T cell activation, which might contribute to an inhibition of atherosclerosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the ELAN-Fonds of the University of Erlangen-Nuremberg (to N.B. and H.-M.L.), and from the German Research Association (DFG) and the German Ministry for Education and Research (BMBF) to H.-M.L.

² Address correspondence and reprint requests to Dr. Norbert Blank, Medizinische Klinik V, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail address: Norbert.Blank{at}med.uni-heidelberg.de

³ Abbreviations used in this paper: MR, membrane raft; a.u., arbitrary units; CTB, cholera toxin B subunit; GM1, ganglioside; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HPTLC, high performance thin layer chromatography; LAT, linker of activation in T cells; MbCD, methyl--cyclodextrin; pIV-CIITA, promoter (type IV) of CIITA; PFA, paraformaldehyde; PI, propidium iodide; sCD25, soluble CD25; SEB, staphylococcus enterotoxin B.