Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice

TLDR

Liver regeneration after loss of liver mass involves hepatocyte and nonparenchymal cell proliferation to rapidly restore parenchyma. Administering a single preoperative dose of IL‑6 to IL‑6‑deficient mice restored STAT3 binding, gene expression, and hepatocyte proliferation, preventing liver damage. IL‑6‑deficient mice show impaired liver regeneration characterized by hepatocyte necrosis, reduced DNA synthesis, G1‑phase abnormalities, and loss of STAT3, AP‑1, Myc, and cyclin D1 expression.

Abstract

Liver regeneration stimulated by a loss of liver mass leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Mice with targeted disruption of the interleukin-6 (IL-6) gene had impaired liver regeneration characterized by liver necrosis and failure. There was a blunted DNA synthetic response in hepatocytes of these mice but not in nonparenchymal liver cells. Furthermore, there were discrete G 1 phase (prereplicative stage in the cell cycle) abnormalities including absence of STAT3 (signal transducer and activator of transcription protein 3) activation and depressed AP-1, Myc, and cyclin D1 expression. Treatment of IL-6-deficient mice with a single preoperative dose of IL-6 returned STAT3 binding, gene expression, and hepatocyte proliferation to near normal and prevented liver damage, establishing that IL-6 is a critical component of the regenerative response.