title: Interleukin-18 mediates interleukin-1-induced cardiac dysfunction.
abstract: 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.
authors: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia;
authors: Stefano
authors: S
authors: Toldo
authors: Eleonora
authors: E
authors: Mezzaroma
authors: Laura
authors: L
authors: O'Brien
authors: Carlo
authors: C
authors: Marchetti
authors: Ignacio M
authors: IM
authors: Seropian
authors: Norbert F
authors: NF
authors: Voelkel
authors: Benjamin W
authors: BW
authors: Van Tassell
authors: Charles A
authors: CA
authors: Dinarello
authors: Antonio
authors: A
authors: Abbate
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D013599:Systole; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000906:Antibodies; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; C118370:interleukin-18 binding protein
keywords: heart failure; inflammation; interleukins; systolic dysfunction