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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (485)	3/3/2001 2:21:07 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 1169

Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 5, 2871-2876, February 27, 2001 Physiology Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1 Benjamin J. Pomerantz,, Leonid L. Reznikov, Alden H. Harken, and Charles A. Dinarello, Departments of * Surgery and Medicine, University of Colorado Health Sciences Center, Denver, CO 80262 Contributed by Charles A. Dinarello, December 22, 2000 The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia/reperfusion (I/R) 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 I/R resulted in improved contractile function after I/R 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 I/R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg/mg vs. I/R, 26 pg/mg; 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 I/R (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 I/R-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.