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Review
. 2014 Jun 12;20(1):221-9.
doi: 10.2119/molmed.2014.00034.

Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure

Laura C O'Brien  1 , Eleonora Mezzaroma  2 , Benjamin W Van Tassell  2 , Carlo Marchetti  3 , Salvatore Carbone  3 , Antonio Abbate  4 , Stefano Toldo  3
Affiliations
Review

Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure

Laura C O'Brien et al. Mol Med. .

Abstract

Interleukin 18 (IL-18) is a proinflammatory cytokine in the IL-1 family that has been implicated in a number of disease states. In animal models of acute myocardial infarction (AMI), pressure overload, and LPS-induced dysfunction, IL-18 regulates cardiomyocyte hypertrophy and induces cardiac contractile dysfunction and extracellular matrix remodeling. In patients, high IL-18 levels correlate with increased risk of developing cardiovascular disease (CVD) and with a worse prognosis in patients with established CVD. Two strategies have been used to counter the effects of IL-18:IL-18 binding protein (IL-18BP), a naturally occurring protein, and a neutralizing IL-18 antibody. Recombinant human IL-18BP (r-hIL-18BP) has been investigated in animal studies and in phase I/II clinical trials for psoriasis and rheumatoid arthritis. A phase II clinical trial using a humanized monoclonal IL-18 antibody for type 2 diabetes is ongoing. Here we review the literature regarding the role of IL-18 in AMI and heart failure and the evidence and challenges of using IL-18BP and blocking IL-18 antibodies as a therapeutic strategy in patients with heart disease.

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Figures

Figure 1
Figure 1
Overview of IL-18 signaling. Left: Stimulation with pathogen-associated molecular pattern molecules (PAMPs) and/or damage-associated molecular pattern molecules (DAMPs) (priming) followed by ATP’s binding the P2×7 receptor (trigger) results in formation of the inflammasome. Caspase-1 then cleaves pro-IL-1β and pro-IL-18 into their active forms. Right: The active IL-18 binds the IL-18Rα-IL-18Rβ receptor dimer or is sequestered by IL-18BP. Alternately, IL-37 binds IL-18Rα and SIGIRR, resulting in an antiinflammatory signal. After the active receptor complex is formed it recruits MyD88, IRAK, and TRAF6 which activates NFκB signaling causing an induction of secondary inflammatory mediators and increased inducible nitric oxide synthase (iNOS) production resulting in contractile dysfunction. The receptor also activates the PI3K-Akt-GATA4 pathway resulting in hypertrophy, and increases OPN resulting in fibrosis. The question mark in panel B highlights that whether the IL-18-mediated activation of IFN is direct or indirect is unknown.
Figure 2
Figure 2
Structures of the different IL-18BP isoforms. Immunoglobulin (IG) domains are in green, potential binding motifs in red and signal peptide in black (44,45).
Figure 3
Figure 3
The role of IL-18 in β-adrenergic receptor (β-AR) signaling. Decreased response to isoproterenol in mice treated daily with IL-18 (58) indicates a desensitization of β-ARs, however the mechanism is unclear.
Figure 4
Figure 4
Schematic of IL-18 activation and signaling with potential targets for pharmacologic intervention.
See this image and copyright information in PMC

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