Role of regulatory T cells in atheroprotective effects of granulocyte colony-stimulating factor.

We and others have previously reported that granulocyte colony-stimulating factor (G-CSF) prevents left ventricular remodeling and dysfunction after myocardial infarction in animal models and human. We have also reported that G-CSF inhibits the progression of atherosclerosis in animal models, but its precise mechanism is still elusive. So, we examined the effects of G-CSF on atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. Twelve-week-old male ApoE(-/-) mice were subcutaneously administrated with 200 μg/kg of G-CSF or saline once a day for 5 consecutive days per a week for 4 weeks. Atherosclerotic lesion of aortic sinus was significantly reduced in the G-CSF-treated mice compared with the saline-treated mice (35% reduction, P<0.05). G-CSF significantly reduced the expression level of interferon-γ by 31% and increased the expression level of interleukin-10 by 20% in atherosclerotic lesions of aortic sinus. G-CSF increased the number of CD4(+)CD25(+) regulatory T cells in lymph nodes and spleen, and enhanced the suppressive function of regulatory T cells in vitro. G-CSF markedly increased the number of Foxp3-positive regulatory T cells in atherosclerotic lesions of aortic sinus. Administration of anti-CD25 antibody (PC61) that depletes regulatory T cells abrogated these atheroprotective effects of G-CSF. Moreover, in ApoE(-/-)/CD28(-/-) mice, that lack regulatory T cells, the protective effects of G-CSF on atherosclerosis were not recognized. These findings suggest that regulatory T cells play an important role in the atheroprotective effects of G-CSF.