Abstract 17438: Interleukin-18 Mediates Interleukin-1 Induced Systolic Dysfunction in the Mouse
Background. Interleukin-1 (IL-1) induces left ventricular (LV) systolic dysfunction in the mouse and IL-1 blockade improves LV function in patients with heart failure (HF). Whether the effects of IL-1 are direct or mediated by an IL-1-inducible cytokine such as interleukin-18 (IL-18) is unknown.
Methods. IL-18 mRNA was measured in the heart tissue of the mice after challenge with exogenous IL 1β or plasma from HF patients. In Group 1 mice, IL 1β (100 ng/mouse) was injected intraperitoneally to induce LV systolic dysfunction. Group 2 mice received IL 1β plus IL 18 Binding Protein (IL 18BP) (300 μg/mouse) to neutralize endogenous IL-18. Group 3 mice received only IL-18BP; saline was injected in Group 4 as vehicle controls. Mice in Group 5 received plasma from patients with HF (200µl, known to induce ventricular dysfunction in the mouse) and Group 6 received HF plasma plus IL 18BP. Group 7 were injected with 200µl of plasma from healthy subjects. The LV fractional shortening (FS) was measured using echocardiography at baseline and 4 hours after the treatments. An additional Group 8 received murine IL-18 (800 ng/mouse) intraperitoneally. All groups included 4-8 CD-1 adult male mice (33±1 grams).
Results. IL-18 mRNA was similarly augmented in the hearts of the mice challenged with IL 1β or HF plasma (data not shown). IL 1β and HF plasma induced a significant 20% reduction in LVFS which was prevented with co-treatment with IL-18BP (Figure). Recombinant murine IL-18 induced a reduction in LVFS similar to that induced by IL 1β or HF plasma (Figure).
Conclusion. IL-18 expression is induced in the heart and mediates IL 1β-induced systolic dysfunction. IL-18 blockade may represent a novel strategy for HF therapy. .
- © 2012 by American Heart Association, Inc.