Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses
De-xiu Bu, … , Guillermo García-Cardeña, Andrew H. Lichtman
De-xiu Bu, … , Guillermo García-Cardeña, Andrew H. Lichtman
Published May 3, 2010
Citation Information: J Clin Invest. 2010;120(6):1961-1970. https://doi.org/10.1172/JCI41384.
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Research Article Immunology

Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses

Abstract

The transcription factor kruppel-like factor 2 (KLF2) is required for the quiescent and migratory properties of naive T cells. Statins, a class of HMG-CoA reductase inhibitors, display pleiotropic immunomodulatory effects that are independent of their lipid-lowering capacity and may be beneficial as therapeutic agents for T cell–mediated inflammatory diseases. Statins upregulate KLF2 expression in endothelial cells, and this activity is associated with an antiinflammatory phenotype. We therefore hypothesized that the immunomodulatory effects of statins are due, in part, to their direct effects on T cell KLF2 gene expression. Here we report that lipophilic statin treatment of mouse and human T cells increased expression of KLF2 through a HMG-CoA/prenylation–dependent pathway. Statins also diminished T cell proliferation and IFN-γ expression. shRNA blockade of KLF2 expression in human T cells increased IFN-γ expression and prevented statin-induced IFN-γ reduction. In a mouse model of myocarditis induced by heart antigen–specific CD8+ T cells, both statin treatment of the T cells and retrovirally mediated overexpression of KLF2 in the T cells had similar ameliorating effects on disease induction. We conclude that statins reduce inflammatory functions and pathogenic activity of T cells through KLF2-dependent mechanisms, and this pathway may be a potential therapeutic target for cardiovascular diseases.

Authors

De-xiu Bu, Margarite Tarrio, Nir Grabie, Yuzhi Zhang, Hiroyuki Yamazaki, George Stavrakis, Elena Maganto-Garcia, Zachary Pepper-Cunningham, Petr Jarolim, Masanori Aikawa, Guillermo García-Cardeña, Andrew H. Lichtman

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Figure 3

Statins increase human T cell KLF2 expression by a mevalonate/isoprenoid-dependent pathway.

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Statins increase human T cell KLF2 expression by a mevalonate/isoprenoid...
Normal human blood T cells were stimulated with αCD3 (6 hours) or with IL-2 plus PHA for 4 days and/or either simvastatin or pitavastatin for 18 hours, before RNA or cytoplasmic lysate isolation, and (A–C) qRT-PCR analysis or (D) Western blot analysis for KLF2 expression was performed. Simvastatin was used at 10 μM and pitavastatin was used at 1 μM or indicated concentrations. (E) Normal human blood T cells were cultured with vehicle or 10 μM simvastatin alone or with 100 μM mevalonate for 8 hours, before RNA isolation and qRT-PCR analysis of KLF2. (F) Normal human blood T cells were cultured in the presence of vehicle, 20 μM FTI, or 20 μM GGTI for 8 hours, before RNA was isolated from the T cells for qRT-PCR analysis. (A) Data are the mean ± SD from 2 donors. (B) Data are from 1 of 2 donors, with similar results. (C) Data are the mean ± SEM from 3 different donors. *P < 0.05 (ANOVA). (D) Data are from 1 of 2 donors, with similar results. (E and F) Data are means ± SD of triplicate samples from 1 of 2 donors, with similar results.