Atorvastatin interferes with activation of human CD4(+) T cells via inhibition of small guanosine triphosphatase (GTPase) activity and caspase-independent apoptosis.
Although a beneficial effect of hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, i.e. statins, on cell-mediated immunity has been suggested in vivo and in vitro, little is known about the molecular and biochemical events by which statins inhibit T cell proliferation. To address this question, we investigated the effects of atorvastatin (AT) on intracellular cytokine production, T cell activation markers, cell cycle progression and apoptosis in human CD4(+) T cells. AT did not influence intracellular cytokine production after short-term stimulation of whole blood with phorbol myristate acetate (PMA)/ionomycin or superantigen (SEB). In contrast, AT influenced CD45RA to RO switching dose-dependently, as well as CD25 expression, and caused cell cycle arrest in the G1 phase after long-term T cell stimulation. This occurred in conjunction with a reduced expression of cyclin-dependent kinases 2 and 4 and p21(wav1/cip1) and was paralleled by an increased protein expression of p27(kip1). In addition to G1 arrest, increased apoptosis was observed in AT-treated cells. In line with this, the expression of Bcl-xl and pBad were decreased by AT. Apoptosis was independent of caspases 3 and 9 activation. The inhibitory effect of AT on T cell proliferation could be overcome by addition of mevalonic acid or geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate or squalen, suggesting reduced protein prenylation. Activation of Rho, Rac and Ras were strongly reduced in AT-treated T cells, suggesting that impaired geranylation of these molecules might underlie the inhibitory effect of AT on T cell proliferation.
Brinkkoetter
P-T
PT
V. Department of Medicine (Nephrology), University Hospital Mannheim, University of Heidelberg, Germany.
Gottmann
U
U
Schulte
J
J
van der Woude
F J
FJ
Braun
C
C
Yard
B A
BA
D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*
D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053645:Interleukin-2 Receptor alpha Subunit; D011758:Pyrroles; D000069059:Atorvastatin; D020169:Caspases; D020559:Monomeric GTP-Binding Proteins