Role of IL-18 and its signaling in atherosclerosis

Cardiovascular diseases (CVD) including coronary artery disease (CAD) and stroke are the largest cause of worldwide morbidity and mortality, where atherosclerosis is the underlying pathology. Recent investigations of atherosclerosis have focused on the role of inflammation, providing new insights into the mechanism of the disease. Macrophages and T-lymphocytes present in the atherosclerotic lesions produce a wide array of cytokines that can exert both pro- and anti-inflammatory effects. Pro-inflammatory cytokines of the interleukin category are considered to be key players in the chronic vascular inflammation that is typical for atherosclerosis. Various studies support the concept that interleukin-18 (IL-18) is a pro-inflammatory cytokine with pro-atherogenic properties. Previous data in Apo E-/- mice demonstrated that IL-18 accelerates atherosclerosis via interferon gamma (IFN- γ) and CXCL16 expression. IL-18 acts by binding to its receptor IL-18R complex, a heterodimer containing α (IL-1Rrp) chain responsible for extracellular binding of IL-18 and a nonbinding, signal-transducing β (AcPL) chain. IL-18 binding to IL-18Rα is shown to result in upregulation of IL-1R-associated kinase (IRAK) and TRAF-6, resulting in nuclear translocation of nuclear factor kappa-B (NF-κB). Presence of activated NF-κB is shown in coronary arteries of pigs fed a hypercholesterolemic diet, in rat arterial smooth muscle cells after balloon injury and in unstable coronary atherectomies. Recent work has shown that genes involved in the lipid uptake and cholesterol efflux in macrophages, like peroxisome proliferator-activated receptor-γ (PPAR-γ) and Liver-X-receptor-α (LXR-α) regulate the expression of many key genes that are involved in the development and progression of atherosclerosis e.g. cytokines, matrix metalloproteinases (MMPs) and scavenger receptors (CD36, SR-A, SR-B1). MMP-9/MMP-2 (members of gelatinase family) are shown to be one of the effector genes of these nuclear receptors (PPAR-γ and LXR-α). Specifically, a role of MMP-9 in atherosclerosis, plaque instability and rupture has been demonstrated during arterial lesion progression. Thus IL-18 can be strongly viewed as a proatherogenic and pro-inflammatory cytokine, as IL-18 signaling results in upregulation of various pro-inflammatory genes and development of atherosclerotic lesions, thus could be envisaged as a therapeutic target.