The effect of daily administration of IL-18 on cardiac structure and function

Abstract

Recently, the cytokine Interleukin-18 (IL-18) has been shown to be increased as a result of cardiac surgery. Elevated IL-18 has been associated with neurological dysfunction, systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS) post open-heart surgery. The intent of the study contained herein was to determine the effect of IL-18 administration on cardiac function and structure. Eight C57BL/6 female mice were treated daily with 0.5microg/mouse of recombinant IL-18 for 7 days. Long axis echocardiography (ECHO) measurements of the anatomical and hemodynamic function of the heart for all mice were studied 24h after the last dose. The left ventricular wet weights increased from 84 +/- 1 to 93 +/- 3 mg when comparing the placebo (n = 8) with the IL-18 groups, respectively (p = 0.01). With ECHO analysis, IL-18 significantly increased left ventricular (LV) mass, the left atrium dimensions (LA), and the left ventricular posterior wall thickness (LVPW) over the 8-day time period (p < 0.01). There was a 5-fold increase in interstitial cardiac collagen content and a 30% increase in myocyte size in the IL-18 compared with the control groups (p < 0.01). Administration of IL-18 appears to induce interstitial fibrosis and myocyte hypertrophy, resulting in increased ventricular stiffness. Thus, increased IL-18 during and post open-heart surgical procedures may induce left ventricular diastolic dysfunction and affect post-operative outcomes.

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

“…IL-18, by binding to its receptor (IL-18R), activates downstream signals that are common to the IL-1 and TLR pathways; however, the activation of the IL-18R and IL-1R1 receptors has different effects (12,46,48,49). Daily injections of IL-18 induce myocardial fibrosis in the mouse (50,51). As a product of the inflammasome, IL-18 may therefore have a complementary effect with IL-1 on the heart in mediating XRT-induced cardiomyopathy.…”

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

“…Inflammatory cytokines contribute to the pathophysiology of HFPEF (96,99), thus IL-18 is a potential target for HFPEF due to its prohypertrophic and profibrotic effects (56)(57)(58)(59)(60)84,86,87). The chronic prohypertrophic and profibrotic effects of IL-18 in animal studies suggest that a longer duration of IL-18 blockade may prevent, or even reverse, the development of pathologic cardiac hypertrophy; however it also may prevent development of physiologic hypertrophy (53).…”

“…ANP normally is expressed only early in development and its expression in adults is a sign of myocardial hypertrophy (57). Daily administration of IL-18 to healthy mice induces ANP expression in the heart, myocardial hypertrophy, and contractile dysfunction (58,59). IL-18 knockout (KO) mice subjected to pressure overload developed less hypertrophy, which is a key feature of the pathology, but also had worse contractile function (60).…”

High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus

“…However, the role of IL-18 in the glomerulus is striking, as reported previously [29], and an increase in IL-18 may be closely related to injury of the glomerulus. IL-18 accelerates the expression of fibronectin on fibroblasts through the activation of NF-jB, resulting in the promotion of fibrosis [20,30]. IL-18 BP inhibits this effect of IL-18 [21].…”