Critical role of inducible costimulator signaling in the development of arteriosclerosis.
OBJECTIVE
Proliferation and migration of smooth muscle cells (SMCs) and migration and accumulation of monocytes and T cells are landmark events in the development of arteriosclerosis. SMC proliferation in the intima induces interruption of blood flow and results in ischemia and graft rejection. Inducible costimulator (ICOS) is a major costimulator of T cell activation. However, the effect of costimulatory molecules on the formation of neointimal hyperplasia has not been fully elucidated. We examined the role of the ICOS pathway in SMC proliferation.


RESULTS
ICOS ligand (ICOSL) was detected in SMCs stimulated by interleukin (IL)-1beta, and coculture of stimulated SMCs and activated T cells induced SMC proliferation. Inhibition of the ICOS pathway resulted in inhibition of SMC proliferation. In models of transplantation and vascular injury, ICOSL was induced in SMCs in the neointima. Expression of IL-1beta, a key inducer of ICOSL expression, was significantly reduced in mice treated with anti-ICOS antibody or soluble form of ICOS (ICOSIg) and in ICOS-deficient mice. Inhibition of the ICOS pathway significantly suppressed neointimal thickening.


CONCLUSIONS
These results indicate that ICOS on activated T cells contributes to neointimal formation through the regulation of SMC proliferation. These findings provide insights into new therapeutic strategies for arteriosclerosis.
Kosuge
Hisanori
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Suzuki
Jun-ichi
J
Haraguchi
Go
G
Koga
Noritaka
N
Maejima
Yasuhiro
Y
Inobe
Manabu
M
Isobe
Mitsuaki
M
Uede
Toshimitsu
T
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006965:Hyperplasia / Q000473:pathology; D060889:Inducible T-Cell Co-Stimulator Protein; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D053583:Interleukin-1beta