title: IκBNS regulates interleukin-6 production and inhibits neointimal formation after vascular injury in mice.
abstract: OBJECTIVE
  IκBNS regulates a subset of Toll-like receptor (TLR)-dependent genes including interleukin-6 (IL-6) by inhibiting nuclear factor-κB (NF-κB). IL-6 is an inflammatory biomarker for cardiovascular diseases. The aim of this study was to determine whether IκBNS changes arterial inflammation and intimal hyperplasia after vascular injury.
  
  
  RESULTS
  We investigated neointimal formation in IκBNS-deficient (IκBNS(-/-); C57BL/6 background) and wild-type (IκBNS(+/+)) mice 2 weeks after cuff injury. The mean intimal area and the intima/media ratio of IκBNS(-/-) mice increased 89% (8066 ± 1141 vs. 4267 ± 1095 μm(2); P = 0.027) and 100% (0.72 ± 0.13 vs. 0.36 ± 0.09; P = 0.032) compared with IκBNS(+/+) mice. We observed significant up-regulation of TLR4 in injured arteries of IκBNS(-/-) mice. NF-κB activity in the intima of IκBNS(-/-) mice was 5.1-fold higher (P = 0.008) compared with IκBNS(+/+) mice at 7 days post-injury. IL-6 mRNA levels in injured arteries of IκBNS(-/-) mice were 1.8-fold higher (P = 0.002) compared with those of IκBNS(+/+) mice at 3 days post-injury. Vascular smooth muscle cells from IκBNS(-/-) mice showed a significant increase in cell migration compared with those from IκBNS(+/+) mice after IL-6 stimulation in the scratch-wound healing assay. Furthermore, anti-mouse IL-6 receptor antibody (MR16-1) significantly reduced intimal hyperplasia compared with control IgG injection in IκBNS(-/-) mice. These findings suggest that IL-6 participates in the development of neointimal hyperplasia after vascular injury in IκBNS(-/-) mice.
  
  
  CONCLUSIONS
  IκBNS down-regulates TLR4 expression, NF-κB activity, and IL-6 production after vascular injury. IκBNS might suppress intimal hyperplasia caused by vascular inflammation such as atherosclerosis, and restenosis after angioplasty.
authors.affiliation: Department of Internal Medicine 1,  National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513,  Japan.
authors.forename: Tomiharu
authors.initials: T
authors.lastname: Niida
authors.forename: Kikuo
authors.initials: K
authors.lastname: Isoda
authors.forename: Manabu
authors.initials: M
authors.lastname: Kitagaki
authors.forename: Norio
authors.initials: N
authors.lastname: Ishigami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsubara
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000517:prevention & control*; D011506:Proteins / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D002784:Cholesterol; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D051197:Toll-Like Receptor 4; C454819:Nfkbid protein, mouse; C493487:Tlr4 protein, mouse