Mice injected with anti-Fas antibody die within a few hours with total liver destruction due to massive apoptosis of hepatocytes. We show that this is preceded and accompanied by the sequential activation of cysteine proteases of the interleukin 1 beta-converting enzyme (ICE) and CPP32 types in the cytosol of the hepatocytes, and that proCPP32 cleavage and enzymatic activity can be prevented by intravenous injections of the tripeptide N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.fmk), an inhibitor of ICE-like proteases. Four Z-VAD.fmk injections at 1-hour intervals abolished all signs of liver damage after anti-Fas antibody injection and resulted in 100% long-range recovery, without residual tissue damage, from a condition otherwise uniformly fatal within < 3 hours. This treatment was effective even when delayed until some liver DNA degradation was already detectable. Injections of the tetrapeptide Ac-YVAD.cmk, more specific for the ICE-like subfamily of cysteine proteases but less cell permeable, also gave protection, but at higher doses and when injections started before that of anti-Fas antibody. These observations afford a way of temporarily modulating a number of apoptotic processes in vivo and may have important therapeutic implications in some human diseases.
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November 01 1996
Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death.
I Rodriguez,
I Rodriguez
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
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K Matsuura,
K Matsuura
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
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C Ody,
C Ody
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
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S Nagata,
S Nagata
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
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P Vassalli
P Vassalli
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
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I Rodriguez
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
K Matsuura
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
C Ody
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
S Nagata
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
P Vassalli
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1996) 184 (5): 2067–2072.
Citation
I Rodriguez, K Matsuura, C Ody, S Nagata, P Vassalli; Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death.. J Exp Med 1 November 1996; 184 (5): 2067–2072. doi: https://doi.org/10.1084/jem.184.5.2067
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