Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells.
Alcohol is a major cause of both acute and chronic pancreatitis. Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic inflammation and fibrosis. Herein, we examined the effect of ethanol and acetaldehyde on the activation of transcription factors and mitogen-activated protein (MAP) kinases in PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype. PSCs were treated with ethanol and acetaldehyde at clinically relevant concentrations (50 mM and 200 microM, respectively). Ethanol and acetaldehyde activated activator protein-1 but not nuclear factor-kappaB. In addition, they activated three classes of MAP kinases: extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 MAP kinase. Ethanol- and acetaldehyde-induced activation of activator protein-1 and MAP kinases was blocked by the antioxidant N-acetyl-cysteine, suggesting a role of oxidative stress in the signal transduction. Ethanol and acetaldehyde induced alpha1(I) procollagen gene expression but did not induce intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. The acetaldehyde-induced increase of alpha1(I) procollagen gene expression was inhibited by the p38 MAP kinase inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) but not by the MAP kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059). Specific activation of these signal transduction pathways may play a role in the pathogenesis of alcohol-induced pancreatic injury.
Masamune
Atsushi
A
Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan. amasamune@int3.med.tohoku.ac.jp
Kikuta
Kazuhiro
K
Satoh
Masahiro
M
Satoh
Akihiko
A
Shimosegawa
Tooru
T
D000079:Acetaldehyde / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D018808:Transcription Factor AP-1; D000431:Ethanol; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000079:Acetaldehyde; C093642:SB 203580