SourceAmerican Journal of Physiology : Heart and Circulatory Physiology, 306, 7, (2014), pp. H1025-31
Article / Letter to editor
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American Journal of Physiology : Heart and Circulatory Physiology
SubjectRadboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences
Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1beta in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30-50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1beta induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1beta failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1beta induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1beta. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.
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- Faculty of Medical Sciences 
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