Harumi Kondo

Deficiency of Interleukin-1 Receptor Antagonist Induces Aortic Valve Disease in BALB/c Mice

Objective—Interleukin-1 receptor antagonist (IL-1Ra), one of the most important antiinflammatory cytokines, is crucial for homeostasis of the immune system. However, the role of IL-1Ra in aortic valve stenosis (AS) remains poorly understood. Methods and Results—IL-1Ra–deficient (IL-1Ra−/−) mice on the BALB/c background showed increased aortic valve leaflet thickness compared to wild-type mice at the age of 12 weeks (P<0.001). We used peripheral T-cell transplantation to examine the role of T cells in the development of AS. T cells from IL-1Ra−/− but not from wild-type mice induced increased aortic valve thickness in nu/nu mice. Moreover, IL-1Ra−/− T cells produced much higher levels of tumor necrosis factor (TNF)-&agr; in culture supernatants after anti-CD3 antibody stimulation compared to wild-type mice (P<0.001). Finally, we studied the role of TNF-&agr; in the development of AS in IL-1Ra−/− mice by generating double-gene-deficient (TNF-&agr;−/−/IL-1Ra−/−) mice. Interestingly, TNF-&agr;−/−/IL-1Ra−/− mice did not have AS. Conclusion—IL-1Ra deficiency in inflammatory cells induced aortic valve inflammation and TNF-&agr; participates importantly in the development of AS in IL-1Ra−/− mice.

Deficiency of Interleukin-1 Receptor Antagonist Promotes Spontaneous Femoral Artery Aneurysm Formation in Mice

Femoral artery aneurysms (FAAs) are very rare, and their natural history is not well understood. In this study, we sought to analyze the pathogenesis of inflammatory FAAs in interleukin-1 receptor antagonist-deficient (IL-1Ra(-/-)) B6 mice. Systolic arterial pressures and plasma lipid levels of IL-1Ra(-/-) mice and wild-type (WT) mice did not differ significantly. However, IL-1Ra(-/-) mice spontaneously developed fusiform FAAs. Real-time PCR of 9-month-old IL-1Ra(-/-) mice revealed significantly increased mRNA levels of IL-1β (6.6-fold), tumor necrosis factor-α (TNF-α) (12.4-fold), and matrix metalloproteinase-9 (6.0-fold) compared with WT mice. Histological analysis revealed numerous inflammatory cells around the FAAs in IL-1Ra(-/-) mice, and elastin staining showed destruction of both the internal and external elastic lamina in IL-1Ra(-/-) mice. Afterward, macrophage function was studied. After lipopolysaccharide (1 μg/mL) stimulation, IL-1Ra-deficient macrophages produced much higher levels of TNF-α than those from WT mice. Finally, we performed bone marrow cell transplantation. FAAs with many inflammatory cells in the adventitia were detected in several WT mice that received bone marrow cells from IL-1Ra(-/-) mice (44%), but not from WT mice (0%). Our study is the first to demonstrate that IL-1Ra deficiency in inflammatory cells disrupts immune system homeostasis and induces inflammatory FAAs in IL-1Ra(-/-) B6 mice. We believe that these mice will provide much information about the natural history and management of FAAs.