title: Critical role of inducible costimulator signaling in the development of arteriosclerosis.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kosuge
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Go
authors.initials: G
authors.lastname: Haraguchi
authors.forename: Noritaka
authors.initials: N
authors.lastname: Koga
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Manabu
authors.initials: M
authors.lastname: Inobe
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: 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
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D053583:Interleukin-1beta