期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 306, 期 7, 页码 H1025-H1031出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00795.2013
关键词
interleukins; inflammation; heart failure; systolic dysfunction
资金
- American Heart Association (AHA) [13POST16360022, 5150329FN, 13BGIA16120001]
- National Institutes of Health (NIH) [5-R01-AI-015614, 1-R21-CA-171974]
- AHA Scientist Development Grant [10SDG3030051]
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-1 beta 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-1 beta induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1 beta failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1 beta 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-1 beta. 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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