LIVER-FAILURE AND DEFECTIVE HEPATOCYTE REGENERATION IN INTERLEUKIN-6-DEFICIENT MICE

Liver regeneration stimulated by a loss of liver mass leads to hepatoc yte and nonparenchymal cell proliferation and rapid restoration of liv er parenchyma. Mice with targeted disruption of the interleukin-6 (IL- 6) gene had impaired liver regeneration characterized by liver necrosi s and failure. There was a blunted DNA synthetic response in hepatocyt es of these mice but not in nonparenchymal liver cells. Furthermore; t here were discrete G(1) phase (prereplicative stage in the cell cycle) abnormalities including absence of STAT3 (signal transducer and activ ator of transcription protein 3) activation and depressed AP-1, Myc, a nd cyclin D1 expression. Treatment of IL-6-deficient mice with a singl e preoperative dose of IL-6 returned STAT3 binding, gene expression, a nd hepatocyte proliferation to near normal and prevented liver damage, establishing that IL-6 is a critical component of the regenerative re sponse.