Deficiency of Interleukin-1 Receptor Antagonist Promotes Neointimal Formation After Injury

Abstract

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 μm [n=10] versus 9.1±0.7 μm [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-1β 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.