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- Title
Statin-induced Krüppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses.
- Authors
De-xiu Bu; Tarrio, Margarite; Grabie, Nir; Yuzhi Zhang; Yamazaki, Hiroyuki; Stavrakis, George; Maganto-Garcia, Elena; Pepper-Cunningham, Zachary; Jarolim, Petr; Aikawa, Masanori; García-Cardeña, Guillermo; Lichtman, Andrew H.; Bu, De-xiu; Zhang, Yuzhi; García-Cardeña, Guillermo
- Abstract
The transcription factor Krüppel-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-gamma expression. shRNA blockade of KLF2 expression in human T cells increased IFN-gamma expression and prevented statin-induced IFN-gamma 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.
- Subjects
GENETIC transcription; STATINS (Cardiovascular agents); T cells; GENE expression; ANTI-inflammatory agents; DRUG lipophilicity; LABORATORY mice; CARDIOVASCULAR diseases; PROTEIN metabolism; ANIMAL experimentation; ANTILIPEMIC agents; BIOCHEMISTRY; COENZYMES; EPITHELIAL cells; IMMUNOLOGY technique; INFLAMMATION; PHENOMENOLOGY; MICE; PROTEINS; RESEARCH funding; TRANSCRIPTION factors; PHARMACODYNAMICS
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 6, p1961
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI41384