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 expression and synthesis of tumour necrosis factor (TNF), IL1, Fas ligand, several chemokines, and vascular adhesion molecules. Similar to IL1beta, IL18 is synthesised as a biologically inactive precursor molecule lacking a signal peptide. The IL18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease, IL1beta converting enzyme (ICE, or caspase-1). Inhibitors of ICE activity limit the biological activity of IL18 in animals and may be useful in reducing the activity of IL18 in human disease. However, a constitutively secreted IL18 binding protein (IL18BP) exists which functions as a natural inhibitor of IL18 activity. IL18BP binds IL18 with a high affinity (Kd of 400 pM) and, at equimolar ratios, inhibits 50-70% of IL18; at twofold molar excess, IL18BP neutralises nearly all IL18 activity.


METHODS
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 resulted in improved post-I/R contractile function from 35% of control to 76% with IL18BP. Also, IL18BP treatment preserved intracellular tissue creatine kinase levels (by 420%). Because active IL18 requires cleavage of its precursor form by ICE, inhibition of ICE attenuated the depression in contractile force after I/R (from 35% of control compared with 75.8% in treated atrial muscle, p<0.01).


CONCLUSIONS
Myocardial ischaemia is a target for IL18BP and use of IL18BP may thereby reduce ischaemia-induced myocardial dysfunction.
Dinarello
C A
CA
Department of Medicine, University Colorado Health Sciences Centre, Denver 80262, USA.
D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D006325:Heart Atria; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology
D061945:Caspase Inhibitors; D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C118370:interleukin-18 binding protein; C118632:tyrosyl-valyl-alanyl-aspartal; D020170:Caspase 1