Research Papers:

Antagonism of Interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes

Xiao-Wei Zhang, Su Mi, Zhe Li, Ji-Chao Zhou, Jing Xie, Fang Hua, Ke Li, Bing Cui, Xiao-Xi Lv, Jiao-Jiao Yu and Zhuo-Wei Hu _

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Oncotarget. 2017; 8:9922-9934. https://doi.org/10.18632/oncotarget.14266

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Xiao-Wei Zhang1, Su Mi1, Zhe Li1, Ji-Chao Zhou1, Jing Xie1, Fang Hua1, Ke Li2, Bing Cui1, Xiao-Xi Lv1, Jiao-Jiao Yu1, Zhuo-Wei Hu1

1Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Correspondence to:

Zhuo-Wei Hu, email: [email protected]

Keywords: cirrhosis, inflammation, liver injury, neutralizing antibody, p62

Received: August 23, 2016     Accepted: December 01, 2016     Published: December 27, 2016


Interleukin-17A has been identified as a driver of hepatic stellate cell activation and plays a critical role in the pathogenesis of hepatic fibrosis. However, the underlining fibrosis-promoting mechanism of IL-17A is far from understood. Here we aimed to define whether hepatocytes directly respond to IL-17A stimulation and are associated with the development of hepatic fibrosis. The functional significance of IL-17A was evaluated in bile duct ligation (BDL) or thioacetamide (TAA) injection-induced mouse models of hepatic fibrosis. Human cirrhosis and control tissues were obtained from the patients with cirrhosis who received an open surgical repair process. Neutralizing IL-17A promoted the resolution of BDL or TAA-induced acute or chronic inflammation and fibrosis, resulted in a shift of the suppressive immune response in fibrotic liver toward a Th1-type immune response, and restored autophagy activity in both cholestatic and hepatotoxic liver injury induced fibrotic liver tissues, which was accompanied by a significant inhibition of STAT3 phosphorylation. Moreover, we found that IL-17A stimulated the concentration-and time-dependent phosphorylation of STAT3 in AML-12 liver cells. Blocking STAT3 with a specific inhibitor STATTIC or STAT3 siRNA protected from the IL-17A-induced autophagy suppression in AML-12 cells, indicating that STAT3 mediates IL-17A-suppressed autophagy. Administration of IL-10, which activated STAT3 and inhibited autophagy, reversed the therapeutic effect of IL-17A antagonism in vivo. Our study suggests that the IL-17A/STAT3 signaling pathway plays a crucial role in the pathogenesis of hepatic fibrosis through suppressing hepatocellular autophagy and that blocking this pathway may provide therapeutic benefits for the treatment of hepatic fibrosis.

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