Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 24, Issue 2, Pages 1488-1503Publisher
WILEY
DOI: 10.1111/jcmm.14833
Keywords
chronic pancreatitis; Hic-5; NF-kappa B; pancreatic stellate cells; triptolide
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Funding
- National Natural Science Foundation of China [81400657]
- Sichuan Science and Technology Plan Project of China [2018JY0283, 2017SZYZF0015]
- Luzhou Municipal People's Government-Southwest Medical University Science and Technology Strategic Cooperation Applied Basic Research Project [2018LZXNYD-ZK14]
- Southwest Medical University-Luzhou Chinese Medicine Hospital Basic Project [LZZYYY2018P00039]
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Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-kappa B (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as alpha-SMA and Col1a1. Therefore, we determined whether suppressing NF-kappa B/p65 alleviated CP by treating mice with the NF-kappa B/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-kappa B/p65 inhibition. These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis.
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