Dataset Information
IL-11 prevents IFN-?-induced hepatocyte death through selective downregulation of IFN-?/STAT1 signaling and ROS scavenging.
Ontology highlight
ABSTRACT: Aims
Interferon-? (IFN-?) 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-?-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-?, and cell death was evaluated by lactate dehydrogenase release into media. As a result, IL-11 pretreatment effectively suppressed IFN-?-induced hepatocyte death. Since IFN-?-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. IFN-? 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-? pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-? 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-?-induced death via STAT1 signal suppression and ROS scavenging. Further investigation into the mechanisms underlying selective negative feedback regulation of IFN-?/STAT1 signaling compared to IL-11/STAT3 signaling may shed new light on the molecular biology of hepatocytes.
SUBMITTER: Miyawaki A
PROVIDER: S-EPMC6380568 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
IL-11 prevents IFN-γ-induced hepatocyte death through selective downregulation of IFN-γ/STAT1 signaling and ROS scavenging.
PloS one 20190219 2
<h4>Aims</h4>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.<h4>Methods and results</h4>Primary culture mouse hepatoc ...[more]
