NFkappaB inhibition decreases hepatocyte proliferation but does not alter apoptosis in obstructive jaundice.
BACKGROUND
Cholestasis activates nuclear factor kappa B (NFkappaB), which is involved in both hepatocyte proliferation and apoptosis, depending on the cellular microenvironment. We hypothesized that NFkappaB inhibition would decrease hepatocyte proliferation and potentiate hepatocyte apoptosis in a rat model of extrahepatic biliary obstruction.


OBJECTIVE
To determine if NFkappaB inhibition concomitantly decreases hepatocyte proliferation and increases apoptosis in obstructive jaundice.


METHODS
Male Sprague-Dawley rats underwent either sham operation or bile-duct ligation (BDL) combined with portal vein injection of vehicle or 6 x 10(9) particles of an adenovirus carrying either the control luciferase or the IkappaB super-repressor (AdIkappaBSR) transgenes. Liver was harvested 3, 5, and 7 days after sham operation or BDL, and immunohistochemistry for proliferating cell nuclear antigen and terminal dUTP nick end-labeling was performed for detection of DNA synthesis and apoptosis, respectively.


RESULTS
Increased serum total bilirubin and hematoxylin and eosin-stained liver sections confirmed cholestasis in BDL animals. Western blot analysis demonstrated IkappaBSR protein expression in AdIkappaBSR-infected animals only. At day 7, NFkappaB inhibition decreased hepatocyte DNA synthesis in BDL rats compared to both adenovirus carrying the control luciferase and vehicle-treated controls. Apoptosis was increased in BDL vehicle-treated animals compared to sham-operation animals, but NFkappaB inhibition did not alter hepatocyte apoptosis in the BDL group.


CONCLUSIONS
In obstructive cholestasis, NFkappaB is required for hepatocyte proliferation, but does not augment apoptosis.
Bird
Mark A
MA
Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7081, USA.
Black
Dalliah
D
Lange
Patricia A
PA
Samson
Charles M
CM
Hayden
Melissa
M
Behrns
Kevin E
KE
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001652:Bile Ducts / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D002455:Cell Division; D002779:Cholestasis / Q000473:pathology* / Q000628:therapy*; D004195:Disease Models, Animal; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000473:pathology*; D020672:I-kappa B Proteins / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases