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

Abstract

Interleukin (IL)-beta plays a central role in inflammation and atherosclerosis, but levels of IL-1beta, 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. Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1beta, 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 coronary angiography. Levels of IL-1beta, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1beta 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 coronary artery plaque area. Activation of innate immunity changed the balance between IL-1beta and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1beta ratio, was associated with reduced coronary atherosclerosis.