| First Author | Miyawaki A | Year | 2019 |
| Journal | PLoS One | Volume | 14 |
| Issue | 2 | Pages | e0211123 |
| PubMed ID | 30779746 | Mgi Jnum | J:273378 |
| Mgi Id | MGI:6281280 | Doi | 10.1371/journal.pone.0211123 |
| Citation | Miyawaki A, et al. (2019) IL-11 prevents IFN-gamma-induced hepatocyte death through selective downregulation of IFN-gamma/STAT1 signaling and ROS scavenging. PLoS One 14(2):e0211123 |
| abstractText | AIMS: Interferon-gamma (IFN-gamma) 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-gamma-induced death and investigated the molecular mechanisms, particularly focusing on signal crosstalk. METHODS AND RESULTS: Primary culture mouse hepatocytes were treated with IL-11 prior to IFN-gamma, and cell death was evaluated by lactate dehydrogenase release into media. As a result, IL-11 pretreatment effectively suppressed IFN-gamma-induced hepatocyte death. Since IFN-gamma-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. IFN-gamma 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-gamma pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-gamma also upregulated SOCSs. Finally, we demonstrated that IL-11 pretreatment mitigated oxidative stress through increasing expression of ROS scavengers. CONCLUSION: IL-11 protects hepatocytes from IFN-gamma-induced death via STAT1 signal suppression and ROS scavenging. Further investigation into the mechanisms underlying selective negative feedback regulation of IFN-gamma/STAT1 signaling compared to IL-11/STAT3 signaling may shed new light on the molecular biology of hepatocytes. |
