Atorvastatin induces T cell anergy via phosphorylation of ERK1.
Modulation of T cell response is a novel property of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors. Previously we reported the benefits of atorvastatin treatment in experimental autoimmune encephalomyelitis, the murine model of the T cell-mediated autoimmune disorder multiple sclerosis, in which a blockade of the T cell cycle by atorvastatin was attributed to an accumulation of the negative regulator p27(Kip1). We show in this report that, in line with the documented role of p27(Kip1) in T cell anergy, treatment with atorvastatin results in a deficient response to a second productive stimulus in human T cells. This effect of atorvastatin was dependent on HMG-CoA reduction and required IL-10 signaling. Importantly, atorvastatin induced an early and sustained phosphorylation of ERK1, but not ERK2, which was crucial for the induction of anergy. On the basis of the therapeutic impact of HMG-CoA reductase inhibitors, the present findings should pave the way for future therapeutic concepts related to tolerance induction in neuroinflammatory disorders such as multiple sclerosis.
Waiczies
Sonia
S
Institute of Neuroimmunology, Neuroscience Research Center, University Hospital Charité, Berlin, Germany.
Prozorovski
Timour
T
Infante-Duarte
Carmen
C
Hahner
Astrid
A
Aktas
Orhan
O
Ullrich
Oliver
O
Zipp
Frauke
F
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000069059:Atorvastatin; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D017635:Clonal Anergy / Q000187:drug effects* / Q000276:immunology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D002070:Butadienes; D006538:Heptanoic Acids; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C113580:U 0126; D016753:Interleukin-10; D000069059:Atorvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2