Glycochenodeoxycholate (GCDC) inhibits cytokine induced iNOS expression in rat hepatocytes.
BACKGROUND
Although the accumulation of hydrophobic bile acid (e.g., glycine conjugated chenodeoxycholic acid, GCDC) is considered to be an important factor contributing to cholestatic liver dysfunction, its pathogenesis is poorly understood. The purpose of this study was to examine the effect of the bile salt GCDC on the regulation of iNOS expression, a key immune modulator during liver inflammation.


METHODS
GCDC significantly decreased cytokine-stimulated iNOS promoter activity, and both iNOS mRNA and protein expression. GCDC decreased iNOS promoter activity by preventing IkappaB degradation and inhibiting NF-kappaB DNA-binding activity. To explore the role of iNOS in bile salt induced apoptosis, we also examined the effect of NO on caspase-3 activity.


RESULTS
GCDC strongly induced caspase-3 activity, and this increase was abrogated by both exogenous NO exposure and endogenous NO synthesis. Furthermore, adenoviral iNOS (AdiNOS) pre-treatment decreased acute cholestatic-induced liver injury in a rat bile duct ligation model.


CONCLUSIONS
These findings indicate a novel signaling pathway where potentially toxic bile salts down-regulate hepatic iNOS expression. This blockade of the iNOS mediated antiapoptotic phenotype may have important implications in certain liver disorders.
Bucher
Brian T
BT
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Feng
Xuesheng
X
Jeyabalan
Geetha
G
Zhang
Baochun
B
Shao
Lifang
L
Guo
Zhong
Z
Geller
David A
DA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D001651:Cholestasis, Extrahepatic / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008026:Ligation; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; D003902:Detergents; D016328:NF-kappa B; D012333:RNA, Messenger; D005999:Glycochenodeoxycholic Acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3