ICE INHIBITOR YVADCMK IS A POTENT THERAPEUTIC AGENT AGAINST IN-VIVO LIVER APOPTOSIS

In liver, apoptosis is a physiological process involved in the clearan ce of injured cells and in homeostatic control [1]. However, in patien ts with viral fulminant hepatitis or with nonacute liver diseases [2], dramatic liver failure or secondary cirrhosis results from the death of hepatocytes, which express the cell-surface receptor Fas, by apopto sis. To date, treatment of fulminant hepatitis relies mainly on orthot opic liver transplantation, which is limited by immunological complica tions and graft availability. Unravelling the molecular mechanisms tha t underlie acute liver failure could allow the design of an appropriat e therapy. Ligand-bound Fas and tumour necrosis factor alpha (TNF-alph a) induce hepatic apoptosis in mice [3-6]. In various cell types, Fas- or TNF-(a)lpha-induced apoptosis is blocked by viral proteins (such a s p35 and CrmA) as well as by a decoy peptide (YVADcmk) [7-11], sugges ting that these mechanisms of apoptosis involve ICE (interleukin-1 bet a converting enzyme)-like proteases. Here, we report that, in vivo, pr e treatment of mice with YVADcmk protects them from the lethal effect of anti-fas antibody and from liver failure induced by injection of TN F-alpha. Remarkably, YVADcmk administration is also highly effective i n rescuing mice that have been pretreated with anti-fas antibody from rapid death, despite extensive hepatic apoptosis. This dramatic curati ve effect could be of clinical benefit for the treatment of viral and inflammatory liver diseases.