C-Jun Does Not Mediate Hepatocyte Apoptosis Following NFκB Inhibition and Partial Hepatectomy

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Inhibition of the transcription factor nuclear factor kappa B (NFκB) induces marked hepatocyte apoptosis and liver dysfunction after partial hepatectomy (PH) in rats. Hepatocyte apoptosis may be due to direct inhibition of NFκB-induced hepatocyte survival genes or due to indirect increased signaling through the stress-activated protein kinase pathway (SAPK), resulting in increased c-Jun. c-Jun, an AP-1 transcription factor, induces apoptosis in fibroblasts. Our aim was to determine if hepatocyte apoptosis following inhibition of NFκB and partial hepatectomy in rats is due to increased c-Jun. Adult male Sprague–Dawley rats (200 g) were injected intraportally with 6 × 109 PFU adenoviral vector containing luciferase (Ad5Luc) or superrepressor IκB (Ad5IκB) transgene that inhibits NFκB translocation into the nucleus. Two-thirds PH was performed 24 h after vector administration, and the remnant liver was harvested 30 min or 24 h after PH. Northern and Western blots were performed to examine the presence of IκB and c-Jun. A GST c-Jun kinase assay was used to examine Jun-N-terminal kinase (JNK) activity. AP-1 DNA binding activity was assessed by electrophoretic mobility shift assay. TUNEL assay was performed to assess apoptosis. All rats receiving adenoviral vectors expressed the luciferase or superrepressor IκB transgenes. c-Jun mRNA, protein levels, and DNA binding activity were not increased in rats treated with Ad5IκB at 30 min after PH compared to rats injected with Ad5Luc. Jun kinase activity increased following partial hepatectomy, but activity was similar in Ad5Luc- and Ad5IκB-treated animals. AP-1 DNA binding activity was not altered substantially in rats treated with Ad5IκB. The percentage of apoptotic hepatocytes was similar between Ad5Luc- and Ad5IκB-injected animals at 0 h, but livers from Ad5IκB-treated rats had increased apoptosis at 24 h compared to Ad5Luc rats (24% vs. 4%) after PH. Hepatocyte apoptosis after NFκB inhibition and PH is not mediated by increased JNK activity or c-Jun.