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Originally published In Press as doi:10.1074/jbc.M207325200 on October 4, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49220-49229, December 20, 2002
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Liver Protection from Apoptosis Requires Both Blockage of Initiator Caspase Activities and Inhibition of ASK1/JNK Pathway via Glutathione S-Transferase Regulation*

David GilotDagger , Pascal Loyer, Anne Corlu, Denise Glaise, Dominique Lagadic-Gossmann§, Azeddine Atfi, Fabrice Morel§, Hidenori Ichijo||, and Christiane Guguen-Guillouzo

From INSERM U522, Régulation des Equilibres fonctionnels du foie Normal et Pathologique, Avenue de la Bataille Flandre/Dunkerque, Hôpital Pontchaillou, 35033 Rennes, § INSERM U456, Détoxication et Réparation Tissulaire, Faculté de Pharmacie, Avenue Léon Bernard, 35049 Rennes, France,  INSERM U482, 184 Rue du Faubourg Saint-Antoine, Hôpital St-Antoine, Paris 75571, and the || Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Hepatoprotection mediated by free radical scavenging molecules such as dimethyl sulfoxide (Me2SO) arose the question as to whether this effect involved one or several anti-apoptotic signals. Here, using primary cultures of rat hepatocytes and in vivo thioacetamide-induced liver failure, we showed that Me2SO failed to prevent any cleavage of initiator caspase-8 and -9 but constantly inhibited procaspase-3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities. Evidence was recently provided that apoptosis might require both caspase and ASK1/JNK-p38 activities. We demonstrated that this kinase pathway was strongly inhibited in the presence of Me2SO whereas overexpression of ASK1 was able to restore caspase-3 activity and apoptosis. Interestingly, we also found that GST M1/2 and GST A1/2 dropped under apoptotic conditions; furthermore transfection of GST M1, A1, or P1 to cells overexpressing ASK1, abolished caspase-3 activity and restored viability. This role of GSTs was further assessed by showing that their high expression level was tightly associated with inhibition of ASK1 activity in Me2SO-protected hepatocytes. Together, these results demonstrate that Me2SO-mediated hepatoprotection involves a dual inhibition of cleaved initiator caspase and ASK1/JNK-p38 activities. Furthermore, in highlighting the control of apoptosis by GSTs, these data provide new insights for analyzing the complex mechanisms of hepatoprotection.

* This work was supported by the Association pour la Recherche contre le Cancer (ARC grant n°5333), INSERM, and the CNRS.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of a doctoral fellowship from La Ligue Nationale Contre le Cancer. To whom correspondence should be addressed. Tel.: 33-2-99-54-37-37; Fax: 33-2-99-54-01-37; E-mail: david.gilot@rennes.inserm.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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