Interleukin‐6: The dark side of liver regeneration in chronic liver disease
Authors: Andreas Geier, Daniel Jahn, Heike M. Hermanns
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. TO THE EDITOR: Lanton et al. recently reported in this journal that genomic instability provoked during the interleukin‐6 (IL‐6)‐mediated regenerative response could contribute to the tumorigenesis observed in Mdr2 knockout (Mdr2–/–) mice after two‐thirds hepatectomy (PH).1 From the literature, Mdr2–/– mice develop chronic inflammation and severe liver fibrosis within 8 weeks from birth and liver regeneration after surgical resection is substantially delayed by almost 50% beyond 3 months of age. Injection of a neutralizing anti‐IL‐6 antibody immediately postsurgery significantly inhibited hepatocyte cell cycle progression, but prevented the increase in hepatocytes bearing micronuclei—a marker of genomic instability putatively contributing to carcinogenesis. Consequently, the substantial incidence of hepatic tumors in Mdr2–/– mice after hepatectomy was also significantly reduced by perioperative anti‐IL‐6 antibody treatment. Although not determined in this study, it is known from the literature that IL‐6 is increased in plasma shortly after experimental hepatectomy, and there is evidence for signal transducer and activator of transcription (STAT3) activation even beyond 24 hours in the present study. Nine hours post‐PH, serum IL‐6 concentrations were above 3,000 pg/mL in Mdr2–/– mice treated with control immunoglobulin G antibody, but undetectable after IL‐6 antibody administration. Differences in the extent and time course of IL‐6 induction post‐PH in the comparison to healthy wild‐type livers are speculative. It could be hypothesized that the IL‐6 signal may be extended given the delayed restoration of liver mass in inflamed and fibrotic Mdr2–/– livers. Apparent questions raised by the study of Lanton et al. are whether there is a vulnerable phase to allow IL‐6‐mediated genomic instability and whether IL‐6 levels in the liver and plasma are constantly blocked by antibody administration or increase at later time points to support regeneration. Furthermore, it remains open, whether later time points of anti‐IL‐6 antibody injection would have the same effects on tumorigenesis. Mechanistically, two recent publications in this journal elucidated the mechanisms underlying hepatocellular carcinogenesis in two different mouse models. Bergmann et al. demonstrated that IL‐6 trans‐signaling (i.e., by soluble IL‐6Rα [IL‐6receptor alpha]), and not IL‐6 classic signaling (i.e., by membrane‐bound IL‐6Rα), is mandatory for diethylnitrosamine‐induced hepatocellular carcinoma (HCC) by preventing hepatocyte apoptosis and fostering angiogenesis.2 Mitra et al., on the other hand, provided evidence that IL‐6 can support the transformation of normal liver stem cells to metastatic cancer stem cells.3 Therefore, IL‐6 activity appears to be strongly context specific. Taking into account that the vast majority of HCC emerges in patients with chronic liver disease mostly in the cirrhotic stage, the study by Lanton et al.1 gains putative importance for clinical practice. In a recent study in healthy donors undergoing right‐lobe donor hepatectomy for living donor liver transplantation, serum levels of IL‐6 were increased from postoperative day 1 (peak with 700 pg/mL, 7‐fold‐increase compared to baseline) lasting until day 42.4 From the experimental data discussed above, it can be hypothesized that HCC patients with primary tumor resection might have an increased risk of de novo tumor development in their remnant liver tissue at risk. IL‐6‐dependent promotion of tumorigenesis after resection could explain why the proposed salvage strategy of primary tumor resection followed by secondary liver transplantation (SLT) after tumor recurrence fails in a high proportion of patients because of rapid tumor progression. In a recent intention‐to‐treat analysis, SLT was feasible in only one third of HCC patients who recurred after liver resection.5