IκBNS regulates interleukin-6 production and inhibits neointimal formation after vascular injury in mice.

Abstract

AIMS:

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.

METHODS AND 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.

CONCLUSION:

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: Tomiharu Niida, Kikuo Isoda, Manabu Kitagaki, Norio Ishigami, Takeshi Adachi, Osamu Matsubara, Kiyoshi Takeda, Tadamitsu Kishimoto, Fumitaka Ohsuzu
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 93 Issue 2 Pg. 371-9 (Feb 01 2012) ISSN: 1755-3245 [Electronic] England
• PMID: 22135163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IkappaBNS protein, mouse
• Interleukin-6
• Intracellular Signaling Peptides and Proteins
• Proteins
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Cholesterol

Topics

• Animals
• Cell Movement
• Cell Proliferation
• Cholesterol (metabolism)
• Interleukin-6 (biosynthesis)
• Intracellular Signaling Peptides and Proteins
• Macrophages (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Neointima (prevention & control)
• Proteins (physiology)
• Toll-Like Receptor 4 (physiology)