An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins.
Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125, a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 microg/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained JNK activation. Administration of SP600125 diminished JNK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha, and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FHF by downregulating Bad and inhibiting Bid cleavage.
Takamura
Masaaki
M
Department of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan. atmc@hotmail.co.jp <atmc@hotmail.co.jp>
Matsuda
Yasunobu
Y
Yamagiwa
Satoshi
S
Tamura
Yasushi
Y
Honda
Yutaka
Y
Suzuki
Kenji
K
Ichida
Takafumi
T
Aoyagi
Yutaka
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000873:Anthracenes / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005688:Galactosamine / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017093:Liver Failure / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D000873:Anthracenes; D051023:BH3 Interacting Domain Death Agonist Protein; C494820:Bad protein, mouse; C474007:Bax protein (53-86); C494815:Bid protein, mouse; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; C432165:pyrazolanthrone; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases