Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses
Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses
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DOI：
10.1172/jci41384
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Lichtman, Andrew H.
中科院分区：
文献类型：
--
作者：
Bu, De-xiu;Tarrio, Margarite;Lichtman, Andrew H.
转录因子Kruppel-like factor2(KLF2)是初始T细胞静止和迁移所必需的。他汀类药物是一类HMG-CoA还原酶抑制剂，具有多效性免疫调节作用，且不依赖于其降脂能力，可作为T细胞介导性炎症性疾病的治疗药物。他汀类药物上调内皮细胞中KLF2的表达，这种活性与抗炎表型有关。因此，我们假设他汀类药物的免疫调节作用部分是由于它们对T细胞KLF2基因表达的直接影响。在这里，我们报告了脂溶性他汀类药物对小鼠和人类T细胞的作用，通过HMG-CoA/异丙烯化依赖的途径增加了KLF2的表达。他汀类药物还能抑制T细胞的增殖和干扰素-γ的表达。ShRNA阻断KLF2在人T细胞中的表达增加了干扰素-γ的表达，并阻止了他汀类药物诱导的干扰素-γ的降低。在心脏抗原特异性CD8(+)T细胞诱导的小鼠心肌炎模型中，他汀类药物治疗T细胞和逆转录病毒介导的KLF2在T细胞中的过表达在疾病诱导中具有相似的改善作用。我们得出结论，他汀类药物通过KLF2依赖机制降低T细胞的炎症功能和致病活性，该途径可能成为心血管疾病的潜在治疗靶点。
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-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.