Cited by 70Alcohol Consumption and Health EffectsCell death mechanisms and regulationLiver physiology and pathology

Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes

Lee, Youn Ju, Shukla, Shivendra D.·2005·European Journal of Pharmacology

Abstract

We have examined the significance of the activation of c-Jun N-terminal kinase (JNK) and p42/44 mitogen-activated protein kinase (MAPK) by ethanol and acetaldehyde in rat hepatocyte apoptosis. Acetaldehyde induced rapid and transient (15 min) activation of p42/44 MAPK followed by activation of JNK, which remained above control up to 1 h. Ethanol activated JNK for up to 4 h. Both ethanol and acetaldehyde caused apoptosis as determined by DNA fragmentation, caspase-3 activation and 2'[4-ethoxyphenyl]-5-[4-methyl-piperazinyl]-2,5'-bi-1H-benzimidazole (Hoechst 33342) staining. Ethanol-induced apoptosis was blocked by JNK inhibitor 1,9-pyrazoloanthrone (SP600125), indicating that JNK activation is pro-apoptotic. In contrast, acetaldehyde-induced apoptosis was not suppressed by this inhibitor. In fact, SP600125 potentiated acetaldehyde-induced apoptosis, suggesting that JNK activation is anti-apoptotic. Inhibition of p42/44 MAPK by MAPK kinase (MKK1) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), potentiated apoptosis by acetaldehyde or ethanol, suggesting anti-apoptotic role of p42/44 MAPK. The activation of JNK by ethanol or acetaldehyde was insensitive to the genistein (tyrosine kinase inhibitor), GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, protein kinase C [PKC] inhibitor) and N-acetylcysteine (N-AC) (antioxidant), whereas p42/44 MAPK activation by acetaldehyde was inhibited by genistein and GF109203X. Furthermore, p42/44 MAPK activation is not necessary for the JNK activation. In summary, transient activation of JNK by acetaldehyde is anti-apoptotic, whereas sustained activation of JNK by ethanol is pro-apoptotic. The activation of p42/44 MAPK appears to be anti-apoptotic for both ethanol and acetaldehyde. Thus, JNK activation by ethanol and acetaldehyde can be both pro- and anti-apoptotic in hepatocytes.

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Crossref · 10.1016/j.ejphar.2004.12.006

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Authors
Lee, Y. J., & Shukla, S. D.
Affiliations
University of Missouri (US)
Corresponding author
Shukla, Shivendra D.
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2005-01
Volume
508
Issue
1-3
Pages
31-45
ISSN
0014-2999 (ISSN-L)
OpenAlex
W2002240376
Cited by
70
References
66
Citations by year
2024: 1 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 1 · 2015: 3 · 2014: 2 · 2013: 3 · 2012: 6
FWCI
4.90
Type
journal article
Language
en
Open access
closed
Locations
  • European Journal of Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Alcohol Abuse and Alcoholism (AA11962, R01AA011962)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
c-Jun N-terminal kinase, p44/42 MAPK, ethanol, acetaldehyde, hepatocyte apoptosis, SP600125, U0126, MKK1, caspase-3, genistein, protein kinase C, oxidative stress, alcohol-induced liver injury, MAPK signaling, JNK inhibitor, MAPK inhibitors
MeSH terms
Acetaldehyde, Acetylcysteine, Ethanol, Animals, Anthracenes, Butadienes, Cell Nucleus, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Hydrogen Peroxide, Indoles, Male, Maleates, Maleimides, Microscopy, Fluorescence, Nitriles, Time Factors, Blotting, Western, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Buthionine Sulfoximine, Genistein, Mitogen-Activated Protein Kinase 1, Caspases, Hepatocytes, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Rats, Caspase 3, DNA Fragmentation

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