title: Interleukin-1 receptor antagonist originating from bone marrowderived cells and non-bone marrow-derived cells helps to suppress arterial inflammation and reduce neointimal formation after injury.
abstract: OBJECTIVE
  Interleukin-1 receptor antagonist (IL-1Ra) negatively regulates IL-1 signaling by blocking the functional receptor. We previously demonstrated that IL-1Ra-deficient (IL-1Ra-/-) mice exhibit marked neointimal formation after injury. IL-1Ra is expressed on bone marrow (BM)-derived cells as well as non-BM intrinsic arterial cells. However, the importance of various cell types as sources of IL-1Ra remains unknown. The aim of this study was to test the hypothesis that IL-1Ra originating from BM-derived cells and non-BM intrinsic cells helps to suppress both inflammation and neointimal formation after vascular injury using a model of BM cell transplantation (BMT).
  
  
  METHODS
  In order to determine the contribution of IL-1Ra-deficient (Ra-/-) and wild-type (WT) BM cells to neointimal formation, we developed four types of BM chimeric mice (BMT(WT→WT) (n=12), BMT(Ra-/-→WT) (n=12), BMT(WT→Ra-/-) (n=12) and BMT(Ra-/-→Ra-/-) (n=12)). At four weeks after BMT, we induced vascular injury by placing a non-occlusive cuff around the femoral artery. Histological analyses were subsequently performed two weeks after injury.
  
  
  RESULTS
  Neointimal formation was decreased in the BMT(WT→Ra-/-) mice compared with that observed in the BMT(Ra-/-→Ra-/-) mice (p＜0.001), but significantly more so in the BMT(Ra-/-→WT) (p＜0.01) and BMT(WT→WT) (p＜0.01) mice. In contrast, the neointimal formation in the BMT(Ra-/-→WT) mice was significantly increased compared with that noted in the BMT(WT→WT) mice (p＜0.05). In addition, immunostaining revealed that Mac3-positive areas were significantly increased in the BMT(Ra-/-→Ra-/-) mice compared with those seen in the other three groups (p＜0.001), with a significantly decreased percentage of alpha-SMA-positive areas in the neointima in the BMT(Ra-/-→Ra-/-) mice compared with that found in the remaining groups (p＜0.001). Furthermore, IL-1Ra staining demonstrated the IL-1Ra expression in several inflammatory cells in the adventitia in the BMT(WT→WT) and BMT(WT→Ra-/-) mice, compared to the neointima in the BMT(WT→WT) and BMT(Ra-/-→WT) mice.
  
  
  CONCLUSIONS
  The IL-1Ra present in BM-derived cells and non-BM cells helps to suppress arterial inflammation, resulting in decreased neointimal formation after injury. These findings shed new light on the mechanisms underlying the development of atherosclerosis and restenosis after angioplasty.
authors.affiliation: Division of Cardiology, Juntendo University.
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.forename: Koji
authors.initials: K
authors.lastname: Akita
authors.forename: Sarasa
authors.initials: S
authors.lastname: Isobe
authors.forename: Tomiharu
authors.initials: T
authors.lastname: Niida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
mesh_terms: D000818:Animals; D001167:Arteritis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005263:Femoral Artery / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*
chemical_list: C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger