| First Author | Toldo S | Year | 2014 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 306 |
| Issue | 7 | Pages | H1025-31 |
| PubMed ID | 24531812 | Mgi Jnum | J:210478 |
| Mgi Id | MGI:5571238 | Doi | 10.1152/ajpheart.00795.2013 |
| Citation | Toldo S, et al. (2014) Interleukin-18 mediates interleukin-1-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 306(7):H1025-31 |
| abstractText | 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. |
