Neutralization of Interleukin-18 Ameliorates Ischemia/Reperfusion-induced Myocardial Injury

Abstract

For both men and women, ischemic heart disease is one of the leading causes of death in the United States today, and its pathobiology has been attributed to many factors, including proinflammatory cytokines. Interleukin (IL) 2 -18 is a pleiotropic cytokine belonging to the IL-1 family (1-5), whose expression is up-regulated in numerous immune, infectious, and inflammatory conditions (1-5), which may further amplify the inflammatory cascade by inducing additional cytokines, chemokines, and adhesion molecules (1-5). Elevated plasma IL-18 levels have been detected in patients with acute coronary syndromes (6), and a direct correlation between IL-18 levels and the severity of myocardial dysfunction has been reported. Circulating IL-18 levels have been shown to be independent predictors of coronary events in humans, with increased basal levels of IL-18 observed in individuals who later developed coronary events (7). Increased circulating IL-18 levels have also been measured during heart failure as well as in stroke patients (8, 9). IL-18 signals via the IL-18 receptor, a heterodimer consisting of a ligand binding ␣-subunit and a signal-transducing ␤-subunit (10, 11). Binding of IL-18 to IL-18R␣ recruits IL-18R␤, and this activated complex initiates pleiotropic signal transduction events. Similar to IL-1 receptor antagonist that blocks IL-1 signaling, IL-18-binding protein (IL-18BP) binds IL-18 with high affinity, inhibits IL-18 bioavailability (12), neutralizes IL-18 effects, and thus reduces inflammation. Interestingly, transgenic mice overexpressing human IL-18BP exhibit reduced inflammation and disease severity (13).Cytotoxic free radicals and proinflammatory cytokines are produced during ischemia/reperfusion (I/R) injury. Using isolated adult rat cardiomyocytes, we have recently described NF-B-dependent IL-18 and IL-18R␤ expression following hydrogen peroxide and TNF-␣ treatment in vitro (14). Moreover, although IL-18BP gene expression under basal conditions in these cells is undetectable, TNF-␣ and H 2 O 2 each induce IL-18BP mRNA in a delayed but persistent manner (14), which suggests tight regulation of IL-18 bioavailability. However, the precise role of IL-18 in I/R injury and its regulation in vivo are incompletely understood, and the signal transduction path-* This work was supported in part by the Research Service of the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

“…A similar increase was observed in the serum and in the post-infarcted myocardium of mice subjected to experimental ischemia followed by reperfusion (63). The rapid rise in pro-IL-18 mRNA and IL-18 protein was followed by a delayed increase in IL-18BP (62).…”

“…The rapid rise in pro-IL-18 mRNA and IL-18 protein was followed by a delayed increase in IL-18BP (62). The use of an IL-18-neutralizing antibody, given to the mouse 1 h before ischemia, reduced infarct size (63). Furthermore, injection of mesenchymal stem cells derived from mice overexpressing IL-18BP into the coronary artery or myocardium of rats before ischemia resulted in increased left ventricular developed pressure (LVDP), improved ejection fraction and decreased infarct size (64).…”

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

“…Endogenous TNF-α and IL-1 play as a mediator of inflammatory reactions, whereas, IL-10 and TGF-β have cardioprotective effects on myocardial I/R injury. Previous studies demonstrated that the blocking of pro-inflammatory cytokines or the administration of cardioprotective cytokines reduced infarct size [32][33][34][35][36][37]. On the other hand, the increases in IL-4 and IFN-γ are characteristic of the activation of iNKT cells [9].…”

Adipose-derived regenerative cells exert beneficial effects on systemic responses following myocardial ischemia/reperfusion

“…Furthermore, in experimental models, proinflammatory cytokines, such as TNF-a and IL-18 [26], have been shown to significantly increase cardiac rupture and dysfunction through an increase in myocyte apoptosis and infarct size. In this study, it has been demonstrated that the expression of TNF-a and IL-18 was induced following cardiac I/R.…”