Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration

Background & Aims: Liver regeneration after toss of hepatic tissue leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Interleukin (IL)-6 is a key inducer of transcription fact ors involved in liver regeneration. Whenever IL-6 activates target cells, i t binds to a specific IL-6 receptor (IL-6R). The IL-6/IL-6R complex then as sociates with the signal transducer gp130, leading to activation of intrace llular signaling Methods: We have recently-constructed the designer cytokin e Hyper-IL-6 consisting of soluble IL-6R covalently linked to IL-6, which d irectly stimulates gp130 even in the absence of membrane-bound IL-6R. We co mpared the influence of IL-6 and Hyper-IL-6 on liver regeneration after par tial hepatectomy in mice. Results: The IL-6/soluble IL-6 fusion protein Hyp er-IL-6, but not IL-6 alone, led to an earlier onset of hepatocellular prol iferation resulting in an acceleration of liver weight restoration. Also, d uring liver regeneration, soluble IL-6R levels were increased. Conclusions: These results emphasize a central role for IL-6 and soluble IL-6R in liver regeneration and indicate a possible therapeutic potential for the designe r cytokine Hyper-IL-6 in clinical situations associated with liver regenera tion such as acute hepatic failure or resection of chronically damaged live r tissue.