FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension.
FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension.
复制标题
DOI：
10.1161/hypertensionaha.110.162917
复制
发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Mitchell BM
中科院分区：
文献类型：
--
作者：
Chiasson VL;Talreja D;Young KJ;Chatterjee P;Banes-Berceli AK;Mitchell BM
免疫抑制药物他克莫司（FK506）结合FK506结合蛋白12 (FKBP12)，然后抑制钙依赖性磷酸酶钙调磷酸酶，患者接受他克莫司（FK506）治疗，表现出调节性T细胞减少、内皮功能障碍和高血压；然而，其机制以及改变的T细胞极化是否起作用尚不清楚。他克莫司治疗小鼠1周后，小鼠脾脏CD4+/FoxP3+（调节性T细胞）和CD4+/IL-17+（辅助性T细胞）呈剂量依赖性降低，并引起内皮功能障碍和高血压。为了确定其机制，我们将FKBP12小鼠与Tie2-Cre小鼠杂交，产生仅在内皮细胞和造血细胞中缺乏FKBP12的后代（FKBP12EC KO）。考虑到FKBP12在抑制TGF-β受体激活中的作用，tie2 - cre介导的FKBP12缺失增加了TGF-β受体激活和SMAD2/3信号通路。FKBP12EC KO小鼠血管中与内皮细胞活化和炎症相关的基因和蛋白表达增加。血清促炎因子IL-2、IL-6、IFNγ、IL-17a、IL-21和IL-23水平显著升高，提示Th17细胞介导的炎症状态。流式细胞术研究证实了这一点，FKBP12EC小鼠脾细胞CD4+/IL-17+细胞水平显著升高，而CD4+/FoxP3+细胞水平显著降低。此外，FKBP12EC KO小鼠的脾脏显示STAT3激活增加，参与Th17细胞诱导，STAT5激活减少，参与调节性T细胞诱导。FKBP12EC KO小鼠也表现出内皮功能障碍和高血压。这些数据提示他克莫司通过激活内皮细胞和造血细胞中的TGF-β受体，可能通过激活内皮细胞，降低Tregs，增加Th17细胞极化和炎症，导致内皮功能障碍和高血压。
Patients treated with the immunosuppressive drug tacrolimus (FK506), which binds FK506 Binding Protein 12 (FKBP12) then inhibits the calcium-dependent phosphatase calcineurin, exhibit decreased regulatory T cells, endothelial dysfunction, and hypertension; however the mechanisms and whether altered T cell polarization play a role are unknown. Tacrolimus treatment of mice for 1 week dose-dependently decreased CD4+/FoxP3+ (regulatory T cells) and increased CD4+/IL-17+ (T helper 17) cells in the spleen, and caused endothelial dysfunction and hypertension. To determine the mechanisms, we crossed floxed FKBP12 mice with Tie2-Cre mice to generate offspring lacking FKBP12 in endothelial and hematopoietic cells only (FKBP12EC KO). Given FKBP12’s role in inhibiting TGF-β receptor activation, Tie2-Cre-mediated deletion of FKBP12 increased TGF-β receptor activation and SMAD2/3 signaling. FKBP12EC KO mice exhibited increased vascular expression of genes and proteins related to endothelial cell activation and inflammation. Serum levels of the pro-inflammatory cytokines IL-2, IL-6, IFNγ, IL-17a, IL-21, and IL-23 were increased significantly suggesting a Th17 cell-mediated inflammatory state. Flow cytometry studies confirmed this as splenocyte levels of CD4+/IL-17+ cells were increased significantly while CD4+/FoxP3+ cells were decreased in FKBP12EC KO mice. Furthermore, spleens from FKBP12EC KO mice showed increased STAT3 activation, involved in Th17 cell induction, and decreased STAT5 activation, involved in regulatory T cell induction. FKBP12EC KO mice also exhibited endothelial dysfunction and hypertension. These data suggest that tacrolimus, through its activation of TGF-β receptors in endothelial and hematopoietic cells, may cause endothelial dysfunction and hypertension by activating endothelial cells, reducing Tregs, and increasing Th17 cell polarization and inflammation.