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

The proinflammatory cytokine IL-18 was investigated for its role in human m yocardial function. An ischemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Additio n of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 a ctivity, to the perifusate during and after I/R resulted in improved contra ctile function after I/R from 35% of control to 76% with IL-18BP. IL-18BP t reatment also preserved intracellular tissue creatine kinase levels (by 420 %). Steady-state mRNA levels for IL-18 were elevated after I/R, and the con centration of IL-18 in myocardial homogenates was increased (control, 5.8 p g/mg vs. I/R, 26 pg/mg; P < 0.01). Active IL-18 requires cleavage of its pr ecursor form by the IL-1<beta>-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I/R (f rom 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because ca spase 1 also cleaves the precursor IL-1<beta>, IL-1 receptor blockade was a ccomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced c ontractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1 beta play a significant role in I/R-induced human myocardial injury a nd that inhibition of caspase 1 reduces the processing of endogenous precur sors of IL-18 and IL-1 beta and thereby prevents ischemia-induced myocardia l dysfunction.