Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation.
OBJECTIVE
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure. C-jun N-terminal kinase (JNK) is thought to play a central role in APAP-induced liver injury, although its upstream activator has not yet been identified. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family and is important for stress-induced JNK activation. We tested the hypothesis that ASK1 was involved in APAP-induced JNK activation and liver injury.


METHODS
ASK1-deficient (ASK1(-/-)) mice and wild-type (WT) mice were given 300 mg/kg of APAP. Serum alanine aminotransferase levels and liver histology were assessed. To investigate the involvement of ASK1 in direct hepatocellular damage and the subsequent inflammatory response, we used primary hepatocytes and splenocytes from WT and ASK1(-/-) mice.


RESULTS
In ASK1(-/-) mouse liver, APAP toxicity was attenuated significantly and the prolonged activation of JNK was inhibited. In addition, thioredoxin, a direct ASK1 inhibitor, dissociated from ASK1 after APAP overdose with concomitant ASK1 activation. Although the prolonged activation of p38 also was attenuated in ASK1(-/-) mice, the p38 signaling pathway was not likely to be involved in APAP-induced liver injury. Primary hepatocyte culture also revealed that ASK1 and JNK, but not p38, contributed to direct APAP-induced cellular damage.


CONCLUSIONS
Our data suggest that ASK1 is activated by APAP overdose, most likely via a mechanism involving thioredoxin-ASK1 dissociation, and that it plays a role in APAP-induced liver injury through JNK activation.
Nakagawa
Hayato
H
Department of Gastroenterology, University of Tokyo, Hongo, Bunkyo-ku, Tokyo.
Maeda
Shin
S
Hikiba
Yohko
Y
Ohmae
Tomoya
T
Shibata
Wataru
W
Yanai
Ayako
A
Sakamoto
Kei
K
Ogura
Keiji
K
Noguchi
Takuya
T
Karin
Michael
M
Ichijo
Hidenori
H
Omata
Masao
M
D000082:Acetaminophen / Q000506:poisoning*; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D062787:Drug Overdose / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse