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IL-17 Imbalance Promotes the Pyroptosis in Immune-Mediated Liver Injury Through STAT3-IFI16 Axis

  • Wenfang Xu (Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University) ;
  • Yanan Wang (Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University) ;
  • Changzhong Jin (State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University) ;
  • Weiyang Zhang (Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University) ;
  • Jiangnan Chen (Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University) ;
  • Xuefang Chen (Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University) ;
  • Junli Gao (Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School) ;
  • Junshun Gao (Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School) ;
  • Hong Wang (Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School)
  • Received : 2023.08.03
  • Accepted : 2023.12.06
  • Published : 2023.12.31
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Abstract

Autoimmune hepatitis (AIH) affects all age group and occurs mainly in women. Pyroptosis is a novel programmed cell death featured with cell bursting and release of proinflammatory cytokines. A deeper understanding of AIH pathogenesis will contribute to novel therapy for AIH patients. Here, we aimed to investigate the role of IL-17 in immune-mediated liver injury. The levels of cytokines were measured by ELISA, and mRNA levels of STAT3 and IFN gamma-inducible protein 16 (IFI16) were detected by PCR. Expressions of STAT3, IFI16, gasdermin D and cleaved caspase-1 were measured by western-blotting. Immunohistochemical staining and transmission electron microscopy were applied to evaluate liver histopathological changes of the treated mice. Our results showed that the levels of IFI16 was increased in hepatocytes treated with IL-17 protein, and further elevated after STAT3-overexpressed (STAT3-OE) lentivirus treatment. The levels of IFI16 were reduced in hepatocytes treated with IL-17 neutralizing Ab (nAb), but were significantly increased after STAT3-OE treatment. Pyroptosis was observed in hepatocytes treated with IL-17 protein, and further cell damage was observed after STAT3-OE lentivirus treatment. Liver damage was alleviated in mice treated with IL-17 nAb, however sever damage was experienced after STAT3-OE lentivirus treatment. A binding interaction between IFI16 and STAT3 was detected in IL-17 treated hepatocytes. Glutathione transaminase activity was enhanced in concanavalin A-induced AIH mice compared to the control group (p<0.01). IL-17 plays an important role in activating STAT3 and up-regulating IFI16, which may promote the pyroptosis in AIH-related liver injury through STAT3-IFI16 axis.

Keywords

Acknowledgement

This work was supported by grant from the Zhejiang Basic Public Welfare Research Project (LGF20H100001), founded by Zhejiang Provincial Department of Science and Technology.

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