Novel targets for interleukin 18 binding protein

Background-Interleukin 18 (IL18) is related to the IL1 family by structure, receptors, signalling molecules, and function. IL18 induces gene expressio n and synthesis of tumour necrosis factor (TNF), IL1, Fas ligand, several c hemokines, and vascular adhesion molecules. Similar to IL1 beta, IL18 is sy nthesised as a biologically inactive precursor molecule lacking a signal pe ptide. The IL18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease, IL1 beta converting enzyme (ICE, o r caspase-1). Inhibitors of ICE activity limit the biological activity of I L18 in animals and may be useful in reducing the activity of IL18 in human disease. However, a constitutively secreted IL18 binding protein (IL18BP) e xists which functions as a natural inhibitor of IL18 activity. IL18BP binds IL18 with a high affinity (Kd of 400 pM) and, at equimolar ratios, inhibit s 50-70% of IL18; at twofold molar excess, IL18BP neutralises nearly all IL 18 activity. Method-IL18 was investigated for its role in human myocardial function. An ischaemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Results-The addition of IL18BP to the perfusate during and after I/R result ed in improved post-I/R contractile function from 35% of control to 76% wit h IL18BP Also, IL18BP treatment preserved intracellular tissue creatine kin ase levels (by 420%). Because active IL18 requires cleavage of its precurso r form by ICE, inhibition of ICE attenuated the depression in contractile f orce after I/R (from 35% of control compared with 75.8% in treated atrial m uscle, p<0.01). Conclusion-Myocardial ischaemia is a target for IL18BP and use of IL18BP ma y thereby reduce ischaemia-induced myocardial dysfunction.