Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels.
Thromb Haemost
; 104(1): 143-50, 2010 Jul.
Article
em En
| MEDLINE
| ID: mdl-20458432
ABSTRACT
Previous studies showed both pro- and anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dose-dependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/- mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both low- and high-dose FK506 treatment significantly reduced systemic CD3+ and CD4+CD25+ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewing.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tacrolimo
/
Células Th2
/
Aterosclerose
/
Imunossupressores
/
Macrófagos
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article