Pharmacological or genetic inhibition of IL-18 signaling prevented IL-1β-induced left ventricular systolic dysfunction in mice, demonstrating that IL-18 mediates IL-1-induced cardiac dysfunction.
Does IL-18 blockade prevent IL-1-induced left ventricular systolic dysfunction in mice?
IL-18 mediates IL-1-induced left ventricular systolic dysfunction, suggesting IL-18 blockade as a potential targeted therapy for heart failure.
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-1β 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-1β induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1β failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1β 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-1β. 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.
Toldo et al. (2014) studied Heart failure (experimental model). IL-18 blockade (IL-18-binding protein, IL-18-blocking antibody, or genetic deletion) vs. Wild-type mice / no pretreatment was evaluated on Left ventricular systolic dysfunction (LV fractional shortening). Pharmacological or genetic inhibition of IL-18 signaling prevented IL-1β-induced left ventricular systolic dysfunction in mice, demonstrating that IL-18 mediates IL-1-induced cardiac dysfunction.
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