Iimuro Y, Nishiura T, Hellerbrand C, Behrns K E, Schoonhoven R, Grisham J W, Brenner D A
Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
J Clin Invest. 1998 Feb 15;101(4):802-11. doi: 10.1172/JCI483.
Although NFkappaB binding activity is induced during liver regeneration after partial hepatectomy, the physiological consequence of this induction is unknown. We have assessed the role of NFkappaB during liver regeneration by delivering to the liver a superrepressor of NFkappaB activity using an adenoviral vector expressing a mutated form of IkappaBalpha. This adenovirus (Ad5IkappaB) was almost exclusively expressed in the liver and inhibited NFkappaB DNA binding activity and transcriptional activity in cultured cells as well as in the liver in vivo. After partial hepatectomy, infection with Ad5IkappaB, but not a control adenovirus (Ad5LacZ), resulted in the induction of massive apoptosis and hepatocytes as demonstrated by histological staining and TUNEL analysis. In addition, infection with Ad5IkappaB but not Ad5LacZ decreased the mitotic index after partial hepatectomy. These two phenomena, increased apoptosis and failure to progress through the cell cycle, were associated with liver dysfunction in animals infected with the Ad5IkappaB but not Ad5LacZ, as demonstrated by elevated serum bilirubin and ammonia levels. Thus, the induction of NFkappaB during liver regeneration after partial hepatectomy appears to be a required event to prevent apoptosis and to allow for normal cell cycle progression.
尽管在部分肝切除术后肝脏再生过程中NFκB结合活性被诱导，但这种诱导的生理后果尚不清楚。我们通过使用表达突变形式的IκBα的腺病毒载体将NFκB活性的超级抑制剂递送至肝脏，来评估NFκB在肝脏再生中的作用。这种腺病毒（Ad5IκB）几乎仅在肝脏中表达，并在培养细胞以及体内肝脏中抑制NFκB DNA结合活性和转录活性。部分肝切除术后，用Ad5IκB感染而非对照腺病毒（Ad5LacZ），会导致大量凋亡和肝细胞的诱导，这通过组织学染色和TUNEL分析得以证明。此外，用Ad5IκB感染而非Ad5LacZ会降低部分肝切除术后的有丝分裂指数。这两种现象，即凋亡增加和细胞周期进展失败，与感染Ad5IκB而非Ad5LacZ的动物的肝功能障碍相关，这通过血清胆红素和氨水平升高得以证明。因此，部分肝切除术后肝脏再生过程中NFκB的诱导似乎是预防凋亡并允许正常细胞周期进展所必需的事件。
