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Department of Medicine, Centre for Rheumatology, University College London, United Kingdom
Loss of tolerance to self-Ags in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease, is associated with dysregulation of T cell signaling, including the depletion of total levels of lymphocyte-specific protein kinase (Lck) from sphingolipid-cholesterol-enriched membrane microdomains (lipid rafts). Inhibitors of 3-hyroxy-3-methylgluteryl CoA reductase (statins) can modify the composition of lipid rafts, resulting in alteration of T cell signaling. In this study, we show that atorvastatin targets the distribution of signaling molecules in T cells from SLE patients, by disrupting the colocalization of total Lck and CD45 within lipid rafts, leading to a reduction in the active form of Lck. Upon T cell activation using anti-CD3/anti-CD28 in vitro, the rapid recruitment of total Lck to the immunological synapse was inhibited by atorvastatin, whereas ERK phosphorylation, which is decreased in SLE T cells, was reconstituted. Furthermore, atorvastatin reduced the production of IL-10 and IL-6 by T cells, implicated in the pathogenesis of SLE. Thus, atorvastatin reversed many of the signaling defects characteristic of SLE T cells. These findings demonstrate the potential for atorvastatin to target lipid raft–associated signaling abnormalities in autoreactive T cells and provide a rationale for its use in therapy of autoimmune disease.
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 The Arthritis Research Campaign supports EC.J. (Project Grant 13967).
2 Address correspondence and reprint requests to Dr. Elizabeth Jury or Dr. Michael Ehrenstein, Centre for Rheumatology Research, University College London, Windeyer Institute of Medical Science, 46 Cleveland Street, London W1P 4JF, U.K. E-mail addresses: e.jury{at}ucl.ac.uk or m.ehrenstein{at}ucl.ac.uk
3 C.M. and M.R.E. contributed equally to this work.
4 Abbreviations used in this paper: HMG-CoA, 3-hyroxy-3-methylgluteryl CoA; SLE, systemic lupus erythematosus; Lck, lymphocyte-specific protein tyrosine kinase; LAT, linker for activation of T cell; CTB, cholera toxin B; DRM, detergent-resistant membrane.
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