TY - JOUR
T1 - Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling
AU - Czaja, Mark J.
AU - Liu, Hailing
AU - Wang, Yongjun
N1 - Funding Information:
Abbreviations: ROS, reactive oxygen species; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; Z-VAD, Val-Ala-Asp-fluoromethylketone; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; FACS, fluorescence-activated cell sorting; TNF, tumor necrosis factor α; NF-κB, nuclear factor κB. From the Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY. Received November 25, 2002; accepted March 18, 2003. Supported by National Institutes of Health grant DK-44234. Address reprint requests to: Mark J. Czaja, M.D., Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: czaja@aecom.yu.edu; fax: 718-430-8975. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3706-0026$30.00/0 doi:10.1053/jhep.2003.50233
PY - 2003/6/1
Y1 - 2003/6/1
N2 - Oxidative stress has been implicated as a mechanism for a variety of forms of liver injury. Although reactive oxygen species (ROS) may damage cellular macromolecules directly, oxidant-induced cell death may result from redox effects on signal transduction pathways. To understand the mechanisms of hepatocyte death from oxidative stress, the functions of the mitogen-activated protein kinases (MAPKs) were determined during oxidant-induced hepatocyte injury from menadione. Low, nontoxic, and high toxic concentrations of the superoxide generator menadione were established in the RALA255-10G rat hepatocyte cell line. Death from menadione was blocked by catalase and ebselen, indicating that death was secondary to oxidant generation and not arylation. Treatment with a nontoxic menadione concentration resulted in a brief activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In contrast, treatment with a toxic menadione concentration induced a prolonged activation of both ERK and JNK. Chemical inhibition of ERK function sensitized RALA hepatocytes to death from previously nontoxic menadione concentrations in association with sustained JNK activation. Adenoviral expression of a dominant-negative protein for c-Jun, a downstream substrate for JNK, blocked death from menadione. The pro-apoptotic effect of c-Jun was not mediated through the mitochondrial death pathway. In conclusion, RALA hepatocyte resistance to oxidant-induced death from menadione is dependent on ERK, whereas cell death is mediated by AP-1 activation. These findings identify signaling pathways that may be therapeutic targets in the prevention or treatment of oxidant-induced liver injury.
AB - Oxidative stress has been implicated as a mechanism for a variety of forms of liver injury. Although reactive oxygen species (ROS) may damage cellular macromolecules directly, oxidant-induced cell death may result from redox effects on signal transduction pathways. To understand the mechanisms of hepatocyte death from oxidative stress, the functions of the mitogen-activated protein kinases (MAPKs) were determined during oxidant-induced hepatocyte injury from menadione. Low, nontoxic, and high toxic concentrations of the superoxide generator menadione were established in the RALA255-10G rat hepatocyte cell line. Death from menadione was blocked by catalase and ebselen, indicating that death was secondary to oxidant generation and not arylation. Treatment with a nontoxic menadione concentration resulted in a brief activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In contrast, treatment with a toxic menadione concentration induced a prolonged activation of both ERK and JNK. Chemical inhibition of ERK function sensitized RALA hepatocytes to death from previously nontoxic menadione concentrations in association with sustained JNK activation. Adenoviral expression of a dominant-negative protein for c-Jun, a downstream substrate for JNK, blocked death from menadione. The pro-apoptotic effect of c-Jun was not mediated through the mitochondrial death pathway. In conclusion, RALA hepatocyte resistance to oxidant-induced death from menadione is dependent on ERK, whereas cell death is mediated by AP-1 activation. These findings identify signaling pathways that may be therapeutic targets in the prevention or treatment of oxidant-induced liver injury.
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U2 - 10.1053/jhep.2003.50233
DO - 10.1053/jhep.2003.50233
M3 - Article
C2 - 12774020
AN - SCOPUS:0038580372
SN - 0270-9139
VL - 37
SP - 1405
EP - 1413
JO - Hepatology
JF - Hepatology
IS - 6
ER -