Interleukin-18: a potent pro-inflammatory cytokine in atherosclerosis: EXPERT'S PERSPECTIVE

Abstract

This editorial refers to an article by R. Elhage et al . [6][1] published in Cardiovascular Research in 2003. It is accompanied by a retrospective editorial by three of the authors of that original article, R. Elhage et al . (doi:10.1093/cvr/cvs220), as part of this Spotlight on Landmark Papers in Cardiovascular Research . The first report on interleukin-18 (IL-18) in patients with myocardial infarction (MI) triggered a significant interest in understanding the role of this cytokine, widely studied in other types of inflammatory diseases, in atherosclerosis.1 Stable and unstable human carotid atherosclerotic plaques were investigated, and it was found that IL-18 was highly expressed compared with control, normal arteries and that it was mainly localized in plaque macrophages.2 IL-18 receptor (IL-18R) was also up-regulated in plaque macrophages and endothelial cells (ECs), suggesting potential biological effects. Significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques as compared with asymptomatic (stable) plaques.2 Electrotransfer of an expression-plasmid DNA encoding murine IL-18-binding protein (BP) in Apo E−/− mice was shown to prevent atherosclerotic plaque progression, inducing changes in plaque composition [a decrease in macrophages, T cells, cell death, and lipid content and an increase in smooth muscle cell (SMC) and collagen content] and leading to a stable plaque phenotype.3 The expression of functional IL-18 and IL-18R was later reported on isolated ECs, SMCs, and macrophages, with the induction of interferon-γ (IFNγ) expression in SMCs.4 Next, studies in Apo E−/− mice showed that IL-18 administration enhanced atherosclerosis in the mouse ascending aorta and the aortic arch through the release of IFNγ.5 However, the IL-18 knockout proof-of-concept was still missing. The effect of blocking the endogenous production of IL18 upon a background of ongoing atherosclerosis progression remained unknown. This information was provided by the important study reported in the … [1]: #ref-6