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

Aims I kappa BNS regulates a subset of Toll-like receptor (TLR)-dependent genes including interleukin-6 (IL-6) by inhibiting nuclear factor-kappa B (NF-kappa B). IL-6 is an inflammatory biomarker for cardiovascular diseases. The aim of this study was to determine whether I kappa BNS changes arterial inflammation and intimal hyperplasia after vascular injury. Methods and results We investigated neointimal formation in I kappa BNS-deficient (I kappa BNS-/-; C57BL/6 background) and wild-type (I kappa BNS+/+) mice 2 weeks after cuff injury. The mean intimal area and the intima/media ratio of I kappa BNS-/- mice increased 89% (8066 +/- 1141 vs. 4267 +/- 1095 mu m(2); P = 0.027) and 100% (0.72 +/- 0.13 vs. 0.36 +/- 0.09; P = 0.032) compared with I kappa BNS+/+ mice. We observed significant up-regulation of TLR4 in injured arteries of I kappa BNS-/- mice. NF-kappa B activity in the intima of I kappa BNS-/- mice was 5.1-fold higher (P = 0.008) compared with I kappa BNS+/+ mice at 7 days post-injury. IL-6 mRNA levels in injured arteries of I kappa BNS-/- mice were 1.8-fold higher (P = 0.002) compared with those of I kappa BNS+/+ mice at 3 days post-injury. Vascular smooth muscle cells from I kappa BNS-/- mice showed a significant increase in cell migration compared with those from I kappa BNS+/+ 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 I kappa BNS-/- mice. These findings suggest that IL-6 participates in the development of neointimal hyperplasia after vascular injury in I kappa BNS-/- mice. Conclusion I kappa BNS down-regulates TLR4 expression, NF-kappa B activity, and IL-6 production after vascular injury. I kappa BNS might suppress intimal hyperplasia caused by vascular inflammation such as atherosclerosis, and restenosis after angioplasty.