Exogenous interleukin-6 enhances liver regeneration after major and extreme liver resection

Objective: To determine the potential therapeutic benefits of exogenous administration of interleukin-6 (IL-6), hepatocyte growth factor (HGF) or the combination on the hepatic regenerative response in vivo. Methods: Mice were administered recombinant IL-6 alone (400ng/ul or 400ng/hr), HGF alone (400ng/ul or 400ng/hr) or the combination by osmotic mini-pump. Alternatively, mice were injected with cells over-expressing IL-6. Mice were subjected to no surgery, sham surgery, 70% or 90% hepatectomy. Results: Exogenous IL-6 by pump induced liver growth without fat or muscle wasting, resulting in high plasma IL-6 level (1471.6 ± 149.4 pg/ml) versus control (14.5 ± 0.8pg/ml). IL-6 administration by either route increased both total and fractional liver mass and stimulated hepatocyte proliferation, as revealed by increased hepatic mitotic figures, BrdU incorporation and PCNA expression. In contrast, HGF alone did not increase liver mass or PCNA expression, while co-administration of HGF and IL-6 did not increase liver mass or PCNA expression over IL-6 alone. IL-6 also induced expression of the anti-apoptotic factors Bcl-2 and Bcl-xL. IL-6 accelerated liver regeneration and recovery of liver mass, with earlier hepatocyte entry into S phase and decreased expression of pro-apoptotic factors, including caspase-3 and cleaved PARP after 70% hepatectomy. IL-6 also improved survival and accelerated liver growth after 90% hepatectomy. Conclusions: Exogenous IL-6, but not HGF, can induce liver growth in non-injured livers. Furthermore, IL-6 administration can enhance the hepatic regenerative response by increasing hepatocyte proliferation and reducing hepatocyte apoptosis. These findings suggest IL-6 therapy has the potential to enhance liver growth and regeneration in clinical settings.