title: Role of regulatory T cells in atheroprotective effects of granulocyte colony-stimulating factor.
abstract: 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.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Raita
authors.initials: R
authors.lastname: Uchiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kameda
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ueda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D008198:Lymph Nodes / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012850:Sinus of Valsalva / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D018106:CD28 Antigens; D016207:Cytokines; D008055:Lipids; D016179:Granulocyte Colony-Stimulating Factor