Date Published: February 19, 2019
Publisher: Public Library of Science
Author(s): Akimitsu Miyawaki, Yoshiko Iizuka, Hitomi Sugino, Yoshifumi Watanabe, Martin E. Rottenberg.
Interferon-γ (IFN-γ) exhibits hepatotoxicity through signal transducer and activator of transcription 1 (STAT1) activation. On the contrary, interleukin-11 (IL-11) shows tissue-protective effects on various organs including the liver through STAT3 activation. Here, we found that IL-11 pretreatment protects hepatocytes from IFN-γ-induced death and investigated the molecular mechanisms, particularly focusing on signal crosstalk.
Primary culture mouse hepatocytes were treated with IL-11 prior to IFN-γ, and cell death was evaluated by lactate dehydrogenase release into media. As a result, IL-11 pretreatment effectively suppressed IFN-γ-induced hepatocyte death. Since IFN-γ-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. IFN-γ robustly activated STAT1 with its peak at 1 hr after stimulation, which was significantly attenuated by IL-11 pretreatment. Consistently, IL-11 pretreatment impeded mRNA increase of STAT1-downstream molecules promoting cell death, i.e., IRF-1, caspase 1, bak, and bax. 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. Interestingly, however, IFN-γ pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-γ also upregulated SOCSs. Finally, we demonstrated that IL-11 pretreatment mitigated oxidative stress through increasing expression of ROS scavengers.
IL-11 protects hepatocytes from IFN-γ-induced death via STAT1 signal suppression and ROS scavenging. Further investigation into the mechanisms underlying selective negative feedback regulation of IFN-γ/STAT1 signaling compared to IL-11/STAT3 signaling may shed new light on the molecular biology of hepatocytes.
The liver possesses a strong ability to regenerate itself after injury, compared to other organs. For example, 70% hepatectomy results in almost complete recovery in liver mass by 21 days post-operation in mice . 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 . These pathologies lead to fibrosis and, eventually, cirrhosis/carcinogenesis of the liver, which is hardly reversible and requires liver transplantation . Therefore, it is of great importance to protect liver parenchymal cells, namely hepatocytes, from chronic damage in order to prevent liver disease progression.
Although IL-11 has been known to protect the liver in the contexts of acetaminophen-induced and ischemia/reperfusion injury [12–14,17], its role in cytokine-induced hepatocyte damage remained unrevealed. In this study, we addressed the effects of IL-11 on hepatocyte death induced by IFN-γ. As a result, IL-11 pretreatment significantly attenuated IFN-γ-induced hepatocyte death by suppressing STAT1 signaling, while IFN-γ pretreatment showed a negligible effect on IL-11-induced STAT3 activation. Additionally, IL-11 enhanced the ROS scavenging capacity of hepatocytes, which could further support its protective function.