Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

Abstract

The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia͞reperfusion (I͞R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I͞R resulted in improved contractile function after I͞R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I͞R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg͞mg vs. I͞R, 26 pg͞mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1␤-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I͞R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1␤, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1␤ play a significant role in I͞R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1␤ and thereby prevents ischemia-induced myocardial dysfunction.

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

“…Increased levels of IL-18 have been found in various autoimmune and inflammatory diseases including patients with heart failure and coronary artery disease where its levels correlate with disease severity [1][2][3][4][5][6]. In these patients, a concomitant increase in IL-18 binding protein (IL-18BP) is observed [6] IL-18BP is a naturally occurring inhibitor of IL-18, is detected in the plasma of healthy subjects at 10-to 20-fold molar excess over IL-18 [7], and is decreased in patients with myocardial ischemic injury and dilated cardiomyopathy.…”

Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

“…4 IL-1 is also a known myocardial suppressant. [4][5] In AMI, IL-1 is initially released by the ischemic endothelial cells and cardiomyocytes and, later, by the leukocytes infiltrating the myocardium. 6 Although IL-1 leads to leukocyte recruitment, which contributes to infarct healing, IL-1 also promotes cell death in cardiomyocytes.…”

Differences in signaling pathways by IL-1β and IL-18

“…The IL-18 receptor (IL-18R) complex consists of two receptor chains: a ligand-binding chain termed the IL-18R␣ chain and a coreceptor termed IL-18R␤ chain; both chains are required for signaling. Using specific neutralization of IL-18 activity, there is a role for IL-18 in rheumatoid arthritis (8,9), ischemic renal (10), and heart disease (11), as well as atherosclerosis (12).…”