Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury

Background-The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood. Methods and Results-Using IL-1Ra-deficient (IL-1Ra(-/-); backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra(+/+)) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra(-/-) mice increased by 249% (31.8 +/- 2.9 mum [n = 10] versus 9.1 +/- 0.7 mum [n = 10]; P < 0.0001) and 257% (2.5 +/- 0.2 versus 0.7 +/- 0.1; P < 0.0001), respectively, compared with IL-1Ra(+/+) mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1beta and the endogenous inhibitor in the endothelium and inflammatory cells of the adventitia in IL-1Ra(+/+) but not IL-1Ra(-/-) mice. Conclusions-The absence of IL-1Ra promotes neointimal formation in mice after injury. These results suggest that endogenous IL-1Ra may suppress other occlusive vascular responses to injury, such as atherosclerosis and restenosis after angioplasty.