A Functional Interleukin-1 Receptor Antagonist Polymorphism Influences Atherosclerosis Development - The Interleukin-1β:Interleukin-1 Receptor Antagonist Balance in Atherosclerosis -

Background: Interleukin (IL)-beta plays a central role in inflammation and atherosclerosis. but levels of IL-1 beta, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions. are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Ra polymorphism Would increase the understanding of atherosclerosis pathogenesis. Methods and Results: Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1 beta, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three Survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using corollary angiography. Levels of IL-1 beta, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1 beta levels more than IL-1Ra levels (ie. promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean corollary artery plaque area. Conclusions: Activation of innate immunity changed the balance between IL-1 beta and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this. the presence of all IL-IRa intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1 beta ratio, was associated with reduced corollary atherosclerosis. (Circ J 2009; 73: 1531 - 1536)