Secreted IL-1Ra exerts a protective effect on atherosclerotic lesion development in apolipoprotein-E-deficient mice

Background

A large body of evidence implicates interleukin (IL)-1, a proinflammatory cytokine, in the pathogenesis of a variety of human inflammatory disorders such as rheumatoid arthritis (RA). RA patients experience a markedly increased frequency of cardiovascular disease. IL-1 is expressed within the endothelium of atherosclerotic plaques and may participate in inflammatory mechanisms of atherogenesis. IL-1 receptor antagonist (IL-1Ra) is a natural IL-1 inhibitor. The term 'IL-1Ra' refers to four different isoforms, one of which is secreted (sIL-1Ra) and the other three of which are intracellular (icIL-1Ra1, 2, 3). sIL-1Ra competitively inhibits receptor binding of IL-1. In patients with RA, the administration of recombinant human sIL-1Ra ameliorates the clinical parameters of disease activity and decreases the progression of joint damage.

Objective

The purpose of this study was to determine whether sIL-1Ra influences the formation of atherosclerotic plaques in vivo.

Methods

Transgenic mice expressing high amounts of human sIL-1Ra were crossed with apolipoprotein-E-deficient mice (ApoE^-/-), which develop atherosclerotic lesions when fed a high-cholesterol diet, in order to obtain ApoE^-/- IL-1Ra-wild-type and ApoE^-/- IL-1Ra-transgenic mice of identical genetic background. Twelve-week-old males of both groups (n = 6 per group) were fed a cholesterol-rich diet (1.25%) for 10 weeks. Increase in serum lipid profiles (total cholesterol, triglycerides) did not differ between both groups. Development of atherosclerotic lesions was measured as the extent of sudanophilic lesions, by computer image analysis.

Results

The average lesion area within aortic roots was significantly decreased (47%, P < 0.001) in transgenic mice (0.49 ± 0.06 mm²) as compared with controls (0.93 ± 0.05 mm²). The extent of sudanophilic lesions was also reduced within the thoracoabdominal aorta in transgenic mice (-36%). Preliminary analysis of the cellular composition of atherosclerotic plaques showed a decrease in the percentage of macrophage-positive areas (-49%) in IL-1Ra transgenic mice as compared with control mice.

Conclusion

Our results show that sIL-1Ra exerts a protective effect on the progression of atherosclerosis in mice. These findings suggest that the administration of IL-1Ra may also exert beneficial effects on cardiovascular complications in patients with RA.