title: The role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis.
abstract: Acute pancreatitis induces liver injury by upregulating Kupffer cell-derived Fas/FasL; on the other hand, acute pancreatitis induces apoptosis of Kupffer cells via NF-kappaB-dependent pathways. The balance between upregulation of Fas/FasL and Fas/FasL-induced apoptosis of its originator cell may determine the severity of pancreatitis-related liver injury. The aim of our study was to determine the role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. Acute pancreatitis was induced in NIH Swiss mice by a choline-deficient ethionine-supplement (CDE) diet. In vitro mouse Kupffer cell line was transfected with p65 siRNA and treated with pancreatic elastase to mimic pancreatitis. CDE pancreatitis upregulated nuclear translocation of p65 NF-kappaB/RelA, Fas/FasL, caspase-3, and DNA fragmentation in mice livers (all P < 0.001). In vitro, pancreatic elastase mimicked CDE-pancreatitis by upregulating nuclear translocation of p65 NF-kappaB/RelA, Fas/FasL, caspase-3, DNA fragmentation, and apoptosis in Kupffer cells (all P < 0.001). Transfection with p65 siRNA attenuated the elastase-induced nuclear translocation of p65 NF-kappaB/RelA, upregulation of Fas/FasL, caspase-3, DNA fragmentation, and apoptosis in Kupffer cells (all P < 0.001). Acute pancreatitis activates p65 NF-kappaB/RelA and induces apoptosis of Kupffer cells. Inhibition of p65NF-kappaB/RelA attenuates elastase-induced upregulation of proapoptotic pathways and apoptosis in Kupffer cells. The ability of Kupffer cells to autoregulate their stress response by inducing self-apoptosis warrants further investigation.
authors.affiliation: Department of Surgery, James A. Haley Veterans Affairs Medical Center, University of South Florida Health Sciences Center, Tampa, Florida 33601, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Peng
authors.forename: Scott F
authors.initials: SF
authors.lastname: Gallagher
authors.forename: Regine
authors.initials: R
authors.lastname: Landmann
authors.forename: Krista
authors.initials: K
authors.lastname: Haines
authors.forename: Michel M
authors.initials: MM
authors.lastname: Murr
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis / Q000502:physiology; D015151:Immunoblotting; D007728:Kupffer Cells / Q000473:pathology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D010195:Pancreatitis / Q000473:pathology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000502:physiology*; D014162:Transfection; D014178:Translocation, Genetic; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases