Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus.
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.
Jury
Elizabeth C
EC
Department of Medicine, Centre for Rheumatology, University College London, United Kingdom. e.jury@ucl.ac.uk
Isenberg
David A
DA
Mauri
Claudia
C
Ehrenstein
Michael R
MR
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000069059:Atorvastatin; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005677:G(M1) Ganglioside / Q000096:biosynthesis; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D017368:Protein Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D011948:Receptors, Antigen, T-Cell; D005677:G(M1) Ganglioside; D000069059:Atorvastatin; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)