Hyper-Interleukin-6 dependent changes in normal and regenerating mouse livers

Although IL-6 is well characterized in the process of liver regeneration, the function of naturally occurring sIL-6R in combination with IL-6 remains to be specified. To address this, we developed a conditional and liver specific mouse model expressing Hyper-IL-6 (HIL-6) protein (sIL-6R covalently linked to IL-6) to study its influence in vitro as well as in healthy and regenerating mouse livers.

Results: Under healthy conditions HIL-6 mice developed a prominent hepatomegaly, the appearance of progenitor markers like CD133, Wilms Tumor Protein 1, A6, Wide Spectrum Cytokeratin and Muscle Pyruvate Kinase as well as an increase in collagen deposition and enhanced levels of Smooth Muscle Actin and Glial Fibrillary Acidic Protein (GFAP). Beside this, proliferating oval cells arise in mice forming atypical ductular reactions. To study the influence of HIL-6 in regenerating mouse livers, we performed 2/3 partial hepatectomy (PHX). Animals with HIL-6 expression displayed a delayed DNA synthesis in comparison to control animals. Additionally a strong proliferation of bile duct cells was observed 48h after PHX.

Our results show that the proliferation capacity of cultured hepatocytes decreased in HIL-6 conditioned medium. In vivo the hepatocyte proliferation index was slightly increased after HIL-6 long term expression. Therefore it can be assumed that the observed hepatomegaly in HIL-6 mice is more a result of hepatocyte hypertrophy and proliferation of non-parenchymal and oval cells rather than proliferation of hepatocytes. Interestingly, HIL-6 mice developed atypical ductular reactions and other probable progenitor populations such as CD133 positive hepatic stellate cells and WT1 positive hepatocytes. Taken together, HIL-6 acts on slowing down the cell cycle of hepatocytes under PHX. In HIL-6 long term expressing mice a proliferative stimulus leads to a conversion of the hepatic tissue and activate the facultative stem- or progenitor cell compartment with a continuous enhanced GFAP expression in hepatic stellate cells. With it, a new model is available to examine the regeneration of the liver by hepatic precursor cells and hepatic stellate cells.