It is widely accepted that dysregulated inflammatory cytokine expression plays a pivotal role in the progression of chronic liver diseases. Therefore, it is of great importance to protect liver parenchymal cells, namely hepatocytes, from chronic damage in order to prevent liver disease progression. These pathologies lead to fibrosis and, eventually, cirrhosis/carcinogenesis of the liver, which is hardly reversible and requires liver transplantation. In contrast, however, the regenerative capacity of the liver is gradually exhausted in situations of cumulative damage, such as chronic virus infection and alcoholic/nonalcoholic steatohepatitis. For example, 70% hepatectomy results in almost complete recovery in liver mass by 21 days post-operation in mice. The liver possesses a strong ability to regenerate itself after injury, compared to other organs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: This study was financially supported by Musashino University. Received: JAccepted: JanuPublished: February 19, 2019Ĭopyright: © 2019 Miyawaki et al. Rottenberg, Karolinska Institutet, SWEDEN Finally, we demonstrated that IL-11 pretreatment mitigated oxidative stress through increasing expression of ROS scavengers.Ĭitation: Miyawaki A, Iizuka Y, Sugino H, Watanabe Y (2019) IL-11 prevents IFN-γ-induced hepatocyte death through selective downregulation of IFN-γ/STAT1 signaling and ROS scavenging. Interestingly, however, IFN-γ pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-γ also upregulated SOCSs. IL-11-mediated suppression of STAT1 signaling was presumably due to upregulation of the suppressor of cytokine signaling (SOCS) genes, which are well-known negative feedback regulators of the JAK/STAT pathway. Consistently, IL-11 pretreatment impeded mRNA increase of STAT1-downstream molecules promoting cell death, i.e., IRF-1, caspase 1, bak, and bax. IFN-γ robustly activated STAT1 with its peak at 1 hr after stimulation, which was significantly attenuated by IL-11 pretreatment. Since IFN-γ-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. As a result, IL-11 pretreatment effectively suppressed IFN-γ-induced hepatocyte death. Primary culture mouse hepatocytes were treated with IL-11 prior to IFN-γ, and cell death was evaluated by lactate dehydrogenase release into media.