Unknown

Dataset Information

0

FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension.


ABSTRACT: Patients treated with the immunosuppressive drug tacrolimus (FK506), which binds FK506 binding protein 12 (FKBP12) and 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 splenic CD4(+)/FoxP3(+) (regulatory T cells), increased splenic CD4(+)/IL-17(+) (T-helper 17) cells, 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 knockout [KO]). Given the role of FKBP12 in inhibiting transforming growth factor-? receptor activation, Tie2-Cre-mediated deletion of FKBP12 increased transforming growth factor-? 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 proinflammatory cytokines IL-2, IL-6, interferon-?, IL-17a, IL-21, and IL-23 were increased significantly, suggesting a T-helper 17 cell-mediated inflammatory state. Flow cytometry studies confirmed this, because splenic levels of CD4(+)/IL-17(+) cells were increased significantly, whereas CD4(+)/FoxP3(+) cells were decreased in FKBP12EC KO mice. Furthermore, spleens from FKBP12EC KO mice showed increased signal transducer and activator of transcription 3 activation, involved in T-helper 17 cell induction, and decreased signal transducer and activator of transcription 5 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 transforming growth factor-? receptors in endothelial and hematopoietic cells, may cause endothelial dysfunction and hypertension by activating endothelial cells, reducing regulatory T cells, and increasing T-helper 17 cell polarization and inflammation.

SUBMITTER: Chiasson VL 

PROVIDER: S-EPMC3108179 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension.

Chiasson Valorie L VL   Talreja Deepa D   Young Kristina J KJ   Chatterjee Piyali P   Banes-Berceli Amy K AK   Mitchell Brett M BM  

Hypertension (Dallas, Tex. : 1979) 20110425 6


Patients treated with the immunosuppressive drug tacrolimus (FK506), which binds FK506 binding protein 12 (FKBP12) and 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 splenic CD4(+)/FoxP3(+) (regulatory T cells), increased splenic CD4(+)/IL-17(+) (T-  ...[more]

Similar Datasets

| S-EPMC4096767 | biostudies-literature
| S-EPMC6080833 | biostudies-literature
| S-EPMC3726153 | biostudies-literature
| S-EPMC7260087 | biostudies-literature
| S-EPMC4849833 | biostudies-other
| S-EPMC8120143 | biostudies-literature
| S-EPMC4530029 | biostudies-literature
| S-EPMC3204361 | biostudies-literature
| S-EPMC6608018 | biostudies-literature
| S-EPMC3533553 | biostudies-literature