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Background: Interleukin-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice on the BALB/c background spontaneously develop inflammatory arthropathy that resembles rheumatoid arthritis in humans. These mice also frequently develop aortitis at the root of the aorta, but the mechanism underlying the development of this disease has not been completely elucidated., Methods and Results: Using IL-1Ra(-/-) mice (backcrossed 8 generations to the BALB/c background) and wild-type mice, we studied the histopathology and examined the immunologic mechanisms involved in the development of aortic inflammation by cell transplantation experiments. Half of the IL-1Ra(-/-) mice developed aortitis at the root of the aorta, with massive infiltration of macrophages and monocytes and loss of elastic lamellae in the aortic media. Left ventricular hypertrophy and mild aortic stenosis were also shown by transthoracic echocardiography. Transplantation of T cells from IL-1Ra(-/-) mice induced aortitis in recipient nu/nu mice. Bone marrow cell transplants from IL-1Ra(-/-) mice also induced aortitis in irradiated wild-type recipient mice. Furthermore, tumor necrosis factor (TNF)-alpha deficiency completely suppressed the development of aortitis in IL-1Ra(-/-) mice, whereas IL-6 deficiency did not affect pathology., Conclusions: These observations suggest that IL-1Ra deficiency in T cells activates them excessively, resulting in the development of aortitis in IL-1Ra(-/-) mice in a TNF-alpha-dependent manner.

Background: In mice that lack interleukin-1 receptor antagonist (IL-1ra), transmural inflammation of the elastic arteries develops at sites of turbulent flow. We described late histopathology previously. Here, we investigate the cellular events in nonlethal arteritis at the aortic root and compare them with Takayasu's arteritis and giant cell arteritis., Methods and Results: IL-1ra-deficient mice were inbred from the original stocks and from BALB/c backcrosses. Disease was ascertained histologically and immunohistologically postmortem at the aortic root. Onset appeared to be stochastic and was not detectably age dependent; in our local Sf3 strain, the half-time of onset was approximately 52 days. Loss of the type I IL-1 receptor suppressed the arteritis. Microvascular activation, as determined by absence of strong E-selectin expression, was absent from preaffected vessels. In mildly affected cases, infiltration was adventitial. In severely affected animals, infiltrates appeared to be active in destroying elastin, but resynthesis of disorganized elastin occurred at closely adjacent sites. Infiltrates consisted predominantly of macrophages but were rich in CD4+-interferon-gamma+ cells, which are likely to represent Th1 cells. Dendritic cells accumulated in lesional areas., Conclusions: The arteritic phenotype of IL-1ra deficiency is mediated by the interleukin-1 receptor and involves effector Th1 cells. The destructive pattern and many of the cellular features of arteritis in IL-1ra-deficient mice resemble the human elastic-vessel arteritides, for which these mice may be a useful animal model.

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 microm [n=10] versus 9.1+/-0.7 microm [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.