RGD Reference Report - Nuclear factor-kappaB mediates Kupffer cell apoptosis through transcriptional activation of Fas/FasL. - Rat Genome Database

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Nuclear factor-kappaB mediates Kupffer cell apoptosis through transcriptional activation of Fas/FasL.

Authors: Peng, Y  Gallagher, SF  Haines, K  Baksh, K  Murr, MM 
Citation: Peng Y, etal., J Surg Res. 2006 Jan;130(1):58-65. Epub 2005 Sep 8.
RGD ID: 1582433
Pubmed: PMID:16154149   (View Abstract at PubMed)
DOI: DOI:10.1016/j.jss.2005.07.030   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FaslgRatinflammatory cell apoptotic process  IGIUniProtKB:P25963 RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FasRattumor necrosis factor receptor activity  IMP  RGD 
FaslgRattumor necrosis factor receptor binding  IMP  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FaslMouseextrinsic apoptotic pathway   ISOFaslg (Rattus norvegicus) RGD 
FaslgRatextrinsic apoptotic pathway   IGIUniProtKB:P25963 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Fas  (Fas cell surface death receptor)
Faslg  (Fas ligand)

Genes (Mus musculus)
Fasl  (Fas ligand)


Additional Information