Document Detail

Nuclear factor-kappaB mediates Kupffer cell apoptosis through transcriptional activation of Fas/FasL.
MedLine Citation:
PMID:  16154149     Owner:  NLM     Status:  MEDLINE    
INTRODUCTION: Nuclear factor (NF)-kappaB is a key transcriptional factor for cell survival, inflammation, and stress response. We demonstrated that Kupffer cell-derived FasL plays a central role in pancreatitis-induced hepatocyte injury. The aim of this study was to determine the role of NF-kappaB in regulating death ligand/receptor pathway in Kupffer cells during conditions that mimic acute pancreatitis. MATERIALS AND METHODS: Tissue cultures of rat Kupffer cells were treated with elastase (1 U/L) to mimic pancreatitis before and after infection with AdIkappaB to block activation of NF-kappaB. Tumor necrosis factor (enzyme-linked immunoassay), Fas/FasL, and caspase-3 (Western), tumor necrosis factor and Fas/FasL mRNA (reverse-transcription polymerase chain reaction), and NF-kappaB DNA binding (electrophoretic mobility shift assay) were determined. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) and DNA fragmentation. Gels were quantified by densitometry. Data (n=3) are mean+/-SEM; student's t test was used for statistical analysis. RESULTS: AdIkappaB infection up-regulated mutated IkappaBalpha that maintained its binding properties to NF-kappaB. Promoter-reporter assay demonstrated that FasL gene promoter was regulated by NF-kappaB. Infection with AdIkappaB attenuated the elastase-induced up-regulation of Fas/FasL (all P<0.01 versus elastase) and NF-kappaB DNA binding but did not affect elastase-induced up-regulation of TNF. AdIkappaB attenuated elastase-induced cleavage of caspase-3, DNA fragmentation and TUNEL staining (all P<0.01 versus elastase). CONCLUSIONS: Inhibition of NF-kappaB DNA binding down-regulates Fas/FasL and attenuates elastase-induced apoptosis; however, it has no effect on TNF production, suggesting that regulation of Fas/FasL and TNF may occur via different pathways. The ability of Kupffer cells to autoregulate their stress response by up-regulating their death ligand/receptor and apoptosis warrants further investigation.
Yanhua Peng; Scott F Gallagher; Krista Haines; Kathryn Baksh; Michel M Murr
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2005-09-08
Journal Detail:
Title:  The Journal of surgical research     Volume:  130     ISSN:  0022-4804     ISO Abbreviation:  J. Surg. Res.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2006-01-03     Completed Date:  2006-02-15     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376340     Medline TA:  J Surg Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  58-65     Citation Subset:  IM    
Department of Surgery, James A. Haley Veterans Affairs Medical Center, and University of South Florida Health Sciences Center, Tampa, Florida 33601, USA.
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MeSH Terms
Acute Disease
Adenoviridae / genetics
Antigens, CD95 / genetics*
Apoptosis / drug effects,  physiology
Caspase 3
Caspases / metabolism
Cell Line, Transformed
Cytomegalovirus / genetics
Fas Ligand Protein
I-kappa B Proteins / genetics,  metabolism
Kupffer Cells / cytology*,  metabolism*
Membrane Glycoproteins / genetics*
NF-kappa B / metabolism*
Pancreatic Elastase / pharmacology
Pancreatitis / metabolism,  physiopathology
Promoter Regions, Genetic / genetics
Rats, Sprague-Dawley
Transcriptional Activation / drug effects,  physiology
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factors / genetics*
Up-Regulation / drug effects,  genetics
Grant Support
Reg. No./Substance:
0/Antigens, CD95; 0/Fas Ligand Protein; 0/I-kappa B Proteins; 0/Membrane Glycoproteins; 0/NF-kappa B; 0/Tnfsf6 protein, rat; 0/Tumor Necrosis Factor-alpha; 0/Tumor Necrosis Factors; 139874-52-5/NF-kappaB inhibitor alpha; EC Elastase; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

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